2. MALE ANDROGENSMALE ANDROGENS
Substances which cause secondary sex characteristicsSubstances which cause secondary sex characteristics
in Malein Male
Natural Androgens:Natural Androgens:
From Testes:From Testes:
• TestosteroneTestosterone
• Dihydrotestosterone (more active) by 5Dihydrotestosterone (more active) by 5 αα-reductase-reductase
From Adrenal cortex: (weak androgens)From Adrenal cortex: (weak androgens)
• DehydroepiandrosteroneDehydroepiandrosterone
• AndrostenedioneAndrostenedione
Androsterone – metabolite of testosteroneAndrosterone – metabolite of testosterone
3. TestosteroneTestosterone
Produced from cholesterolProduced from cholesterol
primarily by Leydig cells inprimarily by Leydig cells in
testestestes
Secreted at adult levels duringSecreted at adult levels during
1st trimester1st trimester11, during neonatal, during neonatal
lifelife22, continually after puberty, continually after puberty33
4. Bound in plasma to albumin & sexBound in plasma to albumin & sex
hormone binding globulin (SHBG)hormone binding globulin (SHBG)
Can be converted to the more potent, 5α-Can be converted to the more potent, 5α-
dihydrotestosterone (DHT), which isdihydrotestosterone (DHT), which is
responsible for many of the responses toresponsible for many of the responses to
testosterone in the urogenital tract (e.g.testosterone in the urogenital tract (e.g.
prostate gland hyperplasia)prostate gland hyperplasia)
5. Binds to and activates a single androgenBinds to and activates a single androgen
receptor (AR)receptor (AR)
Androgen receptors are present in manyAndrogen receptors are present in many
tissues including reproductive tissue,tissues including reproductive tissue,
skeletal muscle, brain, kidney etc.skeletal muscle, brain, kidney etc.
6. Testosterone 17-alkyl substitution Methyltestosterone
Fluoxymesterone
• All androgens contain a Testosterone structures
• Testosterone has 19-carbons and in general its a steroidal
structure
8. 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)
9. Biological Effects - TestosteroneBiological Effects - Testosterone
Androgenic Effects:Androgenic Effects:
In the foetus, testosterone promotes development of maleIn the foetus, testosterone promotes development of male
reproductive tract – internal genitalia, vas deferens, epididymis andreproductive 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 external genitalia.primary sexual characteristics (e.g. enlargement of external genitalia.
secondary sexual characteristics (e.g. male body shape, facial/pubicsecondary sexual characteristics (e.g. male body shape, facial/pubic
hair, deeper pitch of voice)hair, deeper pitch of voice)
Adulthood: Baldness, Benign prostatic hyperplasia, ProstaticAdulthood: Baldness, Benign prostatic hyperplasia, Prostatic
cancercancer
Testes:Testes: Promotion of spermatogenesis and maturation of spermPromotion of spermatogenesis and maturation of sperm
Moderately high dose causes testicular atrophy by inhibitingModerately high dose causes testicular atrophy by inhibiting
Gonadotrophin secretionGonadotrophin secretion
10. 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 andOestrogen from testosterone – fuse of bones and
mineralizationmineralization
Muscle building – if aided by exerciseMuscle building – if aided by exercise
Positive nitrogen, minerals and water balance – increasePositive nitrogen, minerals and water balance – increase
in weightin weight
Increase in appetiteIncrease in appetite
Acceleration of erythropoiesisAcceleration of erythropoiesis
12. Mechanism of ActionMechanism of Action
Androgen receptor:Androgen receptor:
Both, testosterone and DH testosterone – act via AndrogenBoth, testosterone and DH testosterone – act via Androgen
receptors (AR) – nuclear receptor super familyreceptors (AR) – nuclear receptor super family
55 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
Estrogen Receptor:
• Teststerone converts to
estrogen by CYP19
• Deficiency of CYP19 and
estrogen receptor – failure to
fuse long bones,
osteoporosis etc.
13. T DHT DHT- R
T- R
R
R
T- R
Nucleus
90%
10%
5- α
reductase
cytoplasm
14. Therapeutic Uses of AndrogensTherapeutic Uses of Androgens
Androgen replacement therapy (ART)Androgen replacement therapy (ART)
ART uses derivatives of testosterone, rather than syntheticART 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 byis 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 testosteronehypothalamic-pituitary disorders (low LH and low testosterone
levels)levels)
Goal: Mimic the normal testosterone concentration as closely as possibleGoal: 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 withIf 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 remainderTreated by androgen replacement therapy (ART), usually for the remainder
of life. The aim is to restore tissue androgen exposure by using the naturalof life. The aim is to restore tissue androgen exposure by using the natural
androgen testosteroneandrogen testosterone
15. Uses – contd.Uses – contd.
2.2. HypopituitarismHypopituitarism
Monitoring at anticipated time of pubertyMonitoring at anticipated time of puberty
2.2. AIDS related muscle wastingAIDS related muscle wasting
3.3. Hereditary angioneurotic edema (methyltestosterone)Hereditary angioneurotic edema (methyltestosterone)
4.4. AgingAging
Misuse:Misuse: involves prescription with no acceptable medicalinvolves 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 eitherno convincing evidence that androgen therapy is either
effective treatment or safe for older men unless thereeffective treatment or safe for older men unless there
is frank androgen deficiencyis frank androgen deficiency
16. Androgens – Adverse EffectsAndrogens – Adverse Effects
Virilization:Virilization:
may occur in women receiving relatively high dosesmay occur in women receiving relatively high doses
for prolonged periods, such as for estrogen-for prolonged periods, such as for estrogen-
dependent mammary carcinomadependent mammary carcinoma
Cholestatic JaundiceCholestatic Jaundice
may be produced by steroids possessing a 17-alphamay 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
17. Anabolic Steroids – TherapeuticAnabolic Steroids – Therapeutic
usesuses
1.1. Catabolic states: Acute illness, severeCatabolic states: Acute illness, severe
trauma, major surgerytrauma, major surgery
2.2. Renal insufficiency – frequency ofRenal 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
20. IntroductionIntroduction
Most estrogen in the female is produced inMost estrogen in the female is produced in
the ovaries by thethe ovaries by the theca internatheca interna and theand the
granulosagranulosa cells of the follicles.cells of the follicles.
22. Regulation of SecretionRegulation of Secretion
Daily secretion: 10 toDaily secretion: 10 to
100 mcg per day100 mcg per day
During pregnancy –During pregnancy –
large quantity bylarge quantity by
placenta – upto 30placenta – upto 30
mg per daymg per day
Post menopausal: 2 –Post menopausal: 2 –
10 mcg per day only10 mcg per day only
23. 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 stratificationVagina: cornification of epithelial cells with thickening and stratification
of epitheliumof epithelium
Ovaries : stimulate follicular growth; small doses cause an increase inOvaries : 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 ofCervix: Rhythmic contractions of uterus and fallopian tube - increase of
cervical mucous and alkaline watery secretion with a lowered viscositycervical 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
25. Other Pharmacological ActionsOther Pharmacological Actions
Bone:Bone: Important for maintaining bone mass – increasedImportant for maintaining bone mass – increased
expression of bone mass proteins (osteocalcin, alkalineexpression of bone mass proteins (osteocalcin, alkaline
phosphatase)phosphatase)
Generation of vit.D3 – induction of renal hydroxylaseGeneration of vit.D3 – induction of renal hydroxylase
enzymeenzyme
OedemaOedema – 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
26. Mechanism of ActionMechanism of Action
2 ERs are –2 ERs are – ERERαα and ERßand 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 cytosolicEntering the target cells and binding to specific cytosolic
receptorsreceptors
The steroid-receptor complex is then translocated to theThe 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
27. Oestrogen - KineticsOestrogen - Kinetics
Bound to plasma protein (SHBG)Bound to plasma protein (SHBG)
Conjugated with glucoronic acid andConjugated with glucoronic acid and
excreted in urineexcreted in urine
Enterohepatic circulation – deconjugationEnterohepatic circulation – deconjugation
in intestinein intestine
28. 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 inDosage: Oestrogen equivalent to 0.625 mg of EE/day in
cyclical mannercyclical manner
Progestin preparation (medroxy progesterone/norethisterone) isProgestin preparation (medroxy progesterone/norethisterone) is
used – 2.5 mg dailyused – 2.5 mg daily
TTS preparations may be preferredTTS preparations may be preferred
30. 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 andMaintenance 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
31. Actions – contd.Actions – contd.
Cervix:Cervix: viscid and cellular secretion – no sperm penetrationviscid and cellular secretion – no sperm penetration
Vagina:Vagina: Pregnancy like changes – leucocyte infiltration andPregnancy like changes – leucocyte infiltration and
cornified epitheliumcornified epithelium
Breast:Breast: Proliferation of acini in mammary glandsProliferation 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: SedationSedation
Respiration:Respiration: StimulationStimulation
Body temperature:Body temperature: rise in temperaturerise in temperature
Pituitary:Pituitary: Weak Gn inhibitor, suppresses ovulation if given duringWeak Gn inhibitor, suppresses ovulation if given during
follicular phasefollicular phase
32. 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 isoformsPR exists in 2 forms – PR-A and PR-B isoforms
(differing activities)(differing activities)
33. Uses of ProgestinsUses of Progestins
ContraceptiveContraceptive
Hormonl replcement therapyHormonl replcement therapy
Dysfunctional Uterine Bleeding: anovulatoryDysfunctional Uterine Bleeding: anovulatory
cyclescycles
Endometriosis: anovulatory hypoestrogenic stateEndometriosis: anovulatory hypoestrogenic state
is created by progesteroneis created by progesterone
Premenstrual syndromePremenstrual syndrome
Threatened and habitual abortionThreatened and habitual abortion
Endometrial carcinomaEndometrial carcinoma
34. Adverse EffectsAdverse Effects
Breast engorgement, headache, rise in body temp.,Breast engorgement, headache, rise in body temp.,
oedema, acne & mood swingsoedema, 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
Notes de l'éditeur
Fetus – HCG causes release testosterone
- not a product of the ovary, estriol is the predominant urinary end product of estrogen metabolism. In the pregnant woman, estriol, as estradiol and estrone, are secreted by the placenta. Displays minimal estrogenic activity.
Increased NO. PGI2 synthesis – hyperinsulinemia prevention by estrogen
Progesterone acts as a Brain anaesthetic. Increase MAO concentration thus producing depression and irritability