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Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
Reproductive endocrinology
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Reproductive endocrinology

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  • 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
  • Transcript

    • 1. REPRODUCTIVEREPRODUCTIVE ENDOCRINOLOGYENDOCRINOLOGY
    • 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
    • 7. 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
    • 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
    • 11. Androgens – Targets of ActionAndrogens – Targets of Action
    • 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
    • 18. Oestrogens
    • 19. OestrogensOestrogens
    • 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.
    • 21. CH3 OH H H H HO ESTRADIOL CH3 H H H HO O ESTRONE CH3 OH H H H HO OH ESTRIOL Oxidized in liver hydroxylation Natural Oestrogens 1. 2. 3.
    • 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
    • 24. Oestrogens PhysiologyOestrogens Physiology
    • 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
    • 29. Progestins
    • 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

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