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Androgens, Oestrogens, Progestins and Contraceptives - drdhriti

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A power point presentation on Pharmacology of Gonadotropins (Gns)

A power point presentation on Pharmacology of Gonadotropins (Gns)

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  • Fetus – HCG causes release testosterone
  • Penile erection occurs when blood swells the corpus cavernosum, an effect facilitated by relaxation of regional smooth muscle. Smooth muscle tone is regulated by cellular Ca2+, which activates the Ca2+/calmodulin (CaM)-dependent enzyme myosin light chain kinase (MLCK), which leads to MLC phosphorylation and contraction. The nitric oxide (NO) pathway leads to relaxation of smooth muscle by stimulating the soluble guanylyl cyclase (sGC), which results in the production of cyclic GMP (cGMP) and the activation of cGMP-dependent protein kinase (PKG). PKG causes smooth-muscle relaxation by mechanisms that are still being defined and that might include a reduction in cytosolic Ca2+ (by enhanced Ca2+ export and/or by reduced inositol trisphosphate (InsP3) receptor-mediated Ca2+ mobilization) and dephosphorylation of myosin light chains (by activation of MLC phosphatase and/or by sequestration of MLCK in a phosphorylated form that is not readily activated by Ca2+/CaM). Viagra® specifically inhibits the breakdown of cellular cGMP by PDE5 (an isoform of phosphodiesterase that is localized to erectile tissue), and thereby prolongs and enhances the effects of NO/cGMP.
  • - 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
  • Perform a clomiphene challenge test , which is sometimes used to evaluate a woman's ovulation and egg quality ( ovarian reserve ). When given early in a woman's menstrual cycle for 5 days, clomiphene elevates a woman's follicle-stimulating hormone (FSH) level. On the next day, an FSH blood level that has dropped back to normal is a sign of a normal ovarian reserve and ovulation. An elevated FSH is a sign of low ovarian reserve. Women with a diminished ovarian reserve can use donor eggs, which greatly improves their chances of giving birth to a healthy child.
  • Progesterone acts as a Brain anaesthetic. Increase MAO concentration thus producing depression and irritability
  • Transcript

    • 1. Androgens, Oestrogens, Progestins and Hormonal Contraceptives Department of Pharmacology NEIGRIHMS, Shillong
    • 2. Introduction
      • Substances which cause secondary sex characteristics in Male
      • Natural Androgens:
        • From Testes:
          • Testosterone (5-12 mg daily)
          • Dihydrotestosterone (more active) by 5 α -reductase
        • From Adrenal cortex: (weak androgens)
          • Dehydroepiandrosterone
          • Androstenedione
      • {Females – 0.25 – 0.5 mg/day (ovary + adrenals)}
        • Androsterone – metabolite of testosterone
      • Synthetic androgens:
        • Methyltestosterone, Fluoxymesterone
        • Propionate and enanthate
    • 3. Testosterone
      • Produced from cholesterol primarily by Leydig cells in testes
      • Secreted at adult levels during 1st trimester 1 , during neonatal life 2 , continually after puberty 3
      • Bound in plasma to albumin & sex hormone binding globulin (SHBG)
      • Can be converted to the more potent, 5α-dihydrotestosterone (DHT), which is responsible for many of the responses to testosterone in the urogenital tract (e.g. prostate gland hyperplasia)
      • Binds to and activates a single androgen receptor (AR)
      • Androgen receptors are present in many tissues including reproductive tissue, skeletal muscle, brain, kidney etc.
      1 2 3
    • 4. Testosterone 17-alkyl substitution Methyltestosterone
        • Fluoxymesterone
      • All androgens contain a Testosterone structures
      • Testosterone has 19-carbons and in general its a steroidal structure
    • 5. 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
    • 6. Regulation 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)
    • 7. Biological Effects - Testosterone
      • Androgenic Effects:
      • In the foetus, testosterone promotes development of male reproductive tract – internal genitalia, vas deferens, epididymis and external genitalia (sex differentiation)
      • During puberty, testosterone promotes development of :
        • primary sexual characteristics (e.g. enlargement of penis, scrotum and testes)
        • secondary sexual characteristics (e.g. male body shape, facial/pubic hair, deeper pitch of voice)
      • Adulthood: Baldness, BHP, Prostatic cancer
      • Testes: Promotion of spermatogenesis and maturation of sperm
      • Moderately high dose causes testicular atrophy by inhibiting Gn secretion
    • 8. Testosterone – anabolic effects
      • Pubertal spurt of growth at puberty – both boy and girl
      • Bone growth – thickness and length
      • Oestrogen from testosterone – fuse of bones and mineralization
      • Muscle building – if aided by exercise
      • Positive nitrogen, minerals and water balance – increase in weight
      • Increase in appetite
      • Acceleration of erythropoiesis
    • 9. Androgens – Targets of Action
    • 10. Mechanism of Action
      • Androgen receptor:
      • Both, testosterone and DH testosterone – act via Androgen receptors (AR) – nuclear receptor super family
      • 5 α -reductase 1 and 2
      • Ligand binding and DNA binding domains
      • Mutations in AR: Incomplete sexual development
        • Kennedy`s disease: in spinal and
        • bulbar muscle atrophy
      • Estrogen Receptor:
      • Teststerone converts to estrogen by CYP19
      • Deficiency of CYP19 and estrogen receptor – failure to fuse long bones, osteoporosis etc.
    • 11. T DHT DHT- R T- R R R T- R Nucleus 90% 10% 5-  reductase cytoplasm
    • 12. Androgen - Pharmacokinetics
      • Absorption: undergoes high first pass metabolism. Therefore IM injections or synthetic preparations are used
      • Transport: highly protein bound
      • (98%, SHBG, albumin)
      • Metabolism:
        • by liver enzymes : androsterone & etiocholanolone
        • excretion by urine after conjugation
        • small quantity of oestrogen also produced from testosterone
      • Methyltestosterone, Fluoxymesterone metabolized slowly
    • 13. Therapeutic Androgen Preparations
      • Testosterone is ineffective orally (inactivated by liver), and is usually given as i.m. injections of testosterone esters
        • Esterification of fatty acid at 17-hydroxyl group
        • Examples- propionate (25-50 mg), enanthate (100 mg depot preparations)
        • Undecanoate in oil - orally
        • effects last for 2-3 weeks
      • Transdermal preparations: Implants, capsules and patches may improve compliance
        • more stable levels and symptoms, effects last for months
    • 14. Therapeutic Uses of Androgens
      • Androgen replacement therapy (ART)
      • ART uses derivatives of testosterone, rather than synthetic Androgens, because they are safe, effective and easy to monitor
      • Androgen deficiency: clinical diagnosis confirmed by hormone assays
        • is usually caused by
          • underlying testicular disorders (high LH, but low testosterone levels)
          • hypothalamic-pituitary disorders (low LH and low testosterone levels)
      • Goal: Mimic the normal testosterone concentration as closely as possible (serum concentration monitoring)
      • If untreated, does not shorten life expectancy, but is associated with significant morbidity (ambiguous genitalia, delayed puberty & infertility)
      • Treated by androgen replacement therapy (ART), usually for the remainder of life. The aim is to restore tissue androgen exposure by using the natural androgen testosterone
    • 15. Uses – contd.
      • Hypopituitarism
        • Monitoring at anticipated time of puberty
      • AIDS related muscle wasting
      • Hereditary angioneurotic edema (methyltestosterone)
      • Ageing
      • Misuse: involves prescription with no acceptable medical indication
      • Examples of misuse include:
        • male infertility
        • male sexual dysfunction or impotence
        • “ male menopause” (andropause)
      • no convincing evidence that androgen therapy is either effective treatment or safe for older men unless there is frank androgen deficiency
    • 16. Androgens – Adverse Effects
      • Virilization:
        • may occur in women receiving relatively high doses for prolonged periods, such as for estrogen-dependent mammary carcinoma
      • Cholestatic Jaundice
        • may be produced by steroids possessing a 17-alpha methyl group – oral Vs parenteral
      • Priapism (sustained erection)
      • Oligospermia
      • Edema--via promotion of salt and water retention.
      • Precocious puberty and short stature
      • Acne
      • Hepatic carcinoma - oral
      • Gynaecomastia – children and liver disease
    • 17. Androgens - contraindications
      • Carcinoma of Prostate and male Breast
      • Liver and Kidney diseases
      • Pregnancy
      • CHF, epilepsy and migraine
    • 18. Anabolic Steroids
      • Synthetic analogues – higher anabolic but lower androgenic activity (1: 3 ratio)
      • Examples;
        • Nandrolone propionate 10-25 mg/ml (10 – 50 mg IM/week) – inj. Durabolin
        • Nandrolone decanoate 25-100 mg/ml (25-100mg/week) – inj. Decadurabolin
        • Stanazolol (2mg tablets (2-6 mg/day)
    • 19. Anabolic Steroids – Therapeutic uses
      • Catabolic states: Acute illness, severe trauma, major surgery
      • Renal insufficiency – frequency of dialysis
      • Osteoporosis – elderly males
      • Suboptimal growth in boys
      • Anaemia
      • Perfomance enhancement
    • 20. Anti-androgens
      • Danazol
      • Cyproterone acetate
      • Flutamide
      • Finasteride attenuated
    • 21. Danazol
      • Ethisterone derivative effective orally
      • FSH & LH release in both sexes decrease –
      • inhibition of testicular/ovarian function
      • Binding of steroids to receptors decrease
      • Weak androgenic, anabolic, progestational & glucocorticoid action
      • Uses:
        • Endometriosis
        • Menorrhagia
        • Fibrocystic breast disease
        • Hereditary angioneurotic oedema
        • Gynecomastia
        • Infertility: attenuated
      • Preparations:
        • 50. 100 and 200 mg. tablets
        • Dose 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
    • 22. Cyproterone acetate
      • Progesterone like activity – inhibits LH causing antiandrogenic action
      • Competes with dihydroteststerone for intracellular receptor
      • Uses:
      • Acne
      • Male pattern of baldness
      • hirusitism
      • Ca. of prostate
      • Virilizing syndrome
      • Precocious puberty
      • Inappropriate behaviour
    • 23. Flutamide
      • Non-steroidal anti-inflammatory and no hormonal activity but specific antiandrogenic action
      • Antagonise androgens by competitive block – 2-hydroxyflutamide
        • Accessory sex organs
        • Pituitary
      • Uses:
      • Cancer of prostate along with GnRH agonist
      • Female hirusitism
      • Dose: 250 mg tds.
    • 24. Finasteride
      • MOA: Competitive inhibitor of 5 α -reductase
        • Selective of 5 α -reductase type-2 isoenzyme
        • Mainly acts on urogenital tract (prostate) – DHT level lowered but not plasma Testosterone level
      • Uses:
        • Benign prostatic hypertrophy – decrease in prostate volume, improved urinary flow, reversion of disease progression
          • Withdrawal results in regrowth – prolonged therapy
        • Male pattern baldness
      • Kinetics: effective orally, metabolized in liver (t1/2 – 4-6 hrs)
      • Side effects: loss of libido, impotence, decreased ejaculation
      • Doses: 5 mg OD (BHP) or 1 mg OD in baldness
    • 25. Erectile Dysfunction Drugs
      • PDE-5 Inhibitors: Sidenafil, tadalafil
        • Nitric oxide (NO) pathway
    • 26. Sidenafil
      • Absorbed orally and half-life is 4 Hrs
      • Inhibits PDE5 in the corpus cavernosa of the penis
      • 50mg 1 h before sexual activity
      • Potentiate nitrate’s hypotension activity
      • Ketoconazole, erythromycin, Verapamil increases its level – due to CYP3A4 inhibition
      • Renal & hepatic disease increases its level
      • Side effects:
      • headache, flushing, dyspepsia, myalgia, loose motion
      • Other Uses: Pulmonary hypertension
    • 27. Oestrogens
    • 28. Oestrogens
    • 29. Introduction
      • Oestrogens include the natural hormones as well as semi-synthetic and synthetic (stilbene) agents
      • Oestrogens are used as hormone:
        • replacement therapy (menopause)
        • in oncology
        • contraceptives
      • Most estrogen in the female is produced in the ovaries by the theca interna and the granulosa cells of the follicles
    • 30. Oxidized in liver hydroxylation Natural Oestrogens 1. 2. 3.
    • 31. Synthetic oestrogens
      • Steroidal:
        • Ethinyl estradiol , Mestranol and Tibolone
      • Nonsteroidal:
        • Diethinylstilbestrol, Hexestrol and Dienestrol
    • 32. Regulation of Secretion
      • Daily secretion: 10 to 100 mcg per day
      • During pregnancy – large quantity by placenta – upto 30 mg per day
      • Post menopausal: 2 – 10 mcg per day only
    • 33. Actions of Oestrogens
      • On sexual organs (primary and secondary sexual characteristics)
      • Brings about pubertal changes in vagina, fallopian tube and uterus – growth
        • Vagina: cornification of epithelial cells with thickening and stratification of epithelium
        • Ovaries : stimulate follicular growth; small doses cause an increase in weight of ovary; large doses cause atrophy
        • Cervix: Rhythmic contractions of uterus and fallopian tube - increase of cervical mucous and alkaline watery secretion with a lowered viscosity (favoring sperm access)
      • Secondary Sex Characters
      • Metabolic effects: Anabolic
    • 34. Oestrogens Physiology
    • 35. Other Pharmacological Actions
      • Bone: Important for maintaining bone mass – increased expression of bone mass proteins (osteocalcin, alkaline phosphatase)
        • Generation of vit.D3 – induction of renal hydroxylase enzyme
      • Oedema – salt and water retention
      • Increased LDL and decreased HDL level
      • Increased coagulability: II, VII, IX and X
      • Lithogenicity of Bile
      • Increased SHBG, TBG and CBG
    • 36. Mechanism of Action
      • 2 ERs are – ER α and ERß
      • ER α - uterus, vagina, breast and blood vessels
      • ERß – Prostate and Ovaries
      • Work via a steroid hormone mechanism.
      • Entering the target cells and binding to specific cytosolic receptors
      • The steroid-receptor complex is then translocated to the nucleus
      • Where it alters gene expression
      • Coactivator proteins and corepressor proteins
    • 37. Oestrogen - Kinetics
      • Absorbed orally, but quick metabolism – natural ones except ethinyl estradiol
      • All are absorbed transdermally
      • Bound to plasma protein (SHBG)
      • Conjugated with glucoronic acid and excreted in urine
      • Enterohepatic circulation – deconjugation in intestine
    • 38. Oestrogen preparations
      • Preferred route is oral, but sometimes parenteral when large doses are required
      • All estrogen preparations are available – tablet and injections
      • Some examples:
        • EE: 0.01, 0.05, 1 mg tab for menopause
        • Conjugated estrogens: 0.625,1.25 mg tab for DUB or injections 25 mg/ml
        • Mestranol: 0.1 mg tabs to convert to EE
        • Estriol succinate: 1mg/gm cream
    • 39. Transdermal Patches
      • Sizes: 5, 10 and 20 sq. cm –
      • 0.025, 0.05 and 1 mg/day
      • Menopausal women
      • Usual dose: 0.5 mg/day
      • Cyclic therapy
      • Estrogen + Progestin patches
    • 40. Therapeutic Uses
      • Hormone Replacement Therapy to Menopause woman
      • Problems of menopause:
        • Vasomotor disturbances
        • Urogenital atrophy
        • Osteoporosis and fractures
        • Dermatological changes
        • Risk of cardiovascular diseases
      • Dosage: Oestrogen equivalent to 0.625 mg of EE/day in cyclical manner
        • Progestin preparation (medroxy progesterone/norethisterone) is used – 2.5 mg daily
        • TTS preparations may be preferred
    • 41. HRT Indications
      • Benefits: (Indications)
        • Vasomotor and other symptoms of perimenopausal period – smallest effective dose
        • Post hysterectomy patients – estrogen only
        • Young woman with premature menopause
        • Prevention of osteoporosis and fractures
      • Facts:
        • No protection against CVS diseases
        • No protection against cognitive decline – may increase
        • Increase in risk of breast cancer, gall stone, migraine
      • Tibolone:
        • Developed specifically for HRT
        • Estrogenic and progestitional property
        • Dose is 2.5 mg daily
    • 42. Selective Estrogen Receptor Modulators (SERMs)
    • 43. Clomiphene Citrate (Antiestrogen)
      • The “Fertility pill” - pure antagonist of ESTROGEN receptor in all human tissues
      • MOA: Gn secretion and FSH
        • Used in women with unexplained infertility or anovulatory infertility
        • Bind to both, ER α and ERß receptors
        • Blocks estrogenic feedback inhibition of pituitary and induces Gn secretion
        • Increase in amount of secretion of FSH/LH at each secretary pulse
        • Creates favorable atmosphere (ovarian stimulation) for ovulation in ovaries
    • 44. Clomiphene Citrate – contd.
      • Dosage:
        • 50 mg OD from 5 th day onwards for 5 days
        • Continued for 2-3 cycles
        • Conception occurs within 4-6 cycles
        • If no, dose increased
      • Other Uses:
        • Assisted reproduction (to develop multiple eggs)
        • Artificial insemination (irregular ovulation)
        • (Clomiphene Challenge Test)
        • Oligospermia (25 mg daily for 6 months – 6 days rest))
    • 45. Tamoxifen (SERM)
      • Actions:
        • Is a competitive antagonist to estrogen at receptors in the breast.
        • Partial agonist at other estrogen receptors (thus minimizing side effects due to estrogen deprivation) - bone, uterus, liver and pituitary
        • Hot flushes – antiestrogenic action
        • Decrease in LDL level but no change in HDL level
        • Improvement in bone mass and lipid profile
      • Kinetics: Absorbed orally and has biphasic half life – 10 Hrs and 7 days – long duration of action
        • Excreted in Bile
        • Dose is 10 to 20 mg BD
    • 46. Tamoxifen – contd.
      • Uses:
        • Breast carcinoma of pre and post menopause
        • Adjuvant therapy in early cases
        • Palliative therapy
      • Side effects.
        • The drug has a low incidence of adverse reactions
        • Hot flashes, nausea, vomiting, rash, menstrual irregularities and bleeding, infrequent depression, headache, hypercalcemia, edema, and blood dyscrasias
        • Less toxic than anticancer drugs
      • Other SERM – Raloxifene, ormeloxifene etc.
        • Raloxifene is estrogen antagonist of breast and endometrium while partial agonist of bone and CVS
    • 47. Aromatase Inhibitors
      • Letrozole, Anastrozole and Exemestane
      • MOA: Letrozole
        • Non steroidal compound, reversible inhibition of aromatization all over the body
        • Suppression of proliferation of estrogen dependant breast carcinoma cells
        • Rapid oral absorption – 100% bioavailability, large Vd, t1/2 – 40 Hrs
      • Uses: Early breast carcinoma and Advanced breast carcinoma
    • 48. Progestins
    • 49. Preparations
      • Progesterone Derivatives:
        • Progesterone, Hydroxyprogesterone Caproate, Medroxyprogesterone acet, Megesterol acetate
      • 19-Nortestosterone derivatives:
        • Norethindrone, Norethynodrel, Lynestrenol, Allylestrenol
      • 3 rd Generation compounds (Gonanes):
        • norgestimate, norgestrel, desogestrel and levonogestrel
      • Micronized formulations – for oral use
    • 50. Actions of Progesterone
      • Uterus:
      • Responsible for Luteal phase of endometrium
      • High level (pregnancy and luteal phase) prevents secretion of gonadotrophins
      • Maintenance of pregnancy – nidation and maintenance of pregnancy
        • Decrease uterine motility
        • Depression of T-cell function and CMI
      • Menstruation
    • 51. Actions – contd.
      • Cervix: viscid and cellular secretion – no sperm penetration
      • Vagina: Pregnancy like changes – leucocyte infiltration and cornified epithelium
      • Breast: Proliferation of acini in mammary glands
        • Prepares breast for lactation together with estrogen
      • Metabolism:
        • impairment of glucose tolerance
        • Counteraction of benefits of oestrogens
      • CNS: Sedation
      • Respiration: Stimulation
      • Body temperature: rise in temperature
      • Pituitary: Weak Gn inhibitor, suppresses ovulation if given during follicular phase
    • 52. Progesterone – contd.
      • MOA:
        • Receptors are confined to female genital tracts, breasts and CNS
        • PRs are present in nucleus of target cells
        • PR exists in 2 forms – PR-A and PR-B isoforms (differing activities)
      • Kinetics:
        • Inactive orally, high first pass metabolism
        • Synthetics are active orally and metbolized slowly
        • Half-life of 8-24 HRs
    • 53. Uses of Progestins
      • Contraceptive
      • Hormonl replcement therapy
      • Dysfunctional Uterine Bleeding: anovulatory cycles
      • Endometriosis: anovulatory hypoestrogenic state is created by progesterone
      • Premenstrual syndrome
      • Threatened and habitual abortion
      • Endometrial carcinoma
    • 54. Adverse Effects
      • Breast engorgement, headache, rise in body temp.,
      • oedema, acne & mood swings
      • Masculinization of external genitalia in the foetus
      • Increased incidences of congenital abnormalities
      • Irregular bleeding or amenorrhea
      • Lower HDL (19-nortestosterone derivatives)
      • Hyperglycaemia
    • 55. Antiprogestin - Mifepristone
      • 19-norsteroid compound – antiprogestational, antiglucocorticoid and antiandrogenic action
      • Actions:
      • Follicular phase: attenuation of Gn discharge – slow follicular development, failure of ovulation
      • Luteal phase: prevents secretory changes brought about by progesterone
      • Late cycle: Blocking of Progesterone action, increased PG release – uterine contraction
      • Sensitization of endometrium to PG – menstruation
      • On Implantation: Blocking of decidution and dislodging of conceptus
      • In Menopause – progestational activity
    • 56. Mifepristone – contd.
      • Kinetics: Absorbed orally and bioavailability is only 25% and half-life is 20-36 hrs
        • CYP3A4
      • Uses:
        • Termination of Pregnancy
        • Cervical priming
        • Postcoital contraceptive
        • Induction of labour: single dose 2 days after midcycle
        • Cushing Syndrome
      • Preparations: Tablet – 200 mg
    • 57. Pharmacology of Hormonal Contraception
    • 58. Methods of Contraception
      • Direct inhibition of spermatogenesis
      • Indirect inhibition of spermatogenesis
      • Immunological techniques (vaccine)
      • Inhibition of ovulation (Hormonal contraceptives)
      • Prevention of fertilization
      • Anti-zygotic drugs
      • Inhibition of implantation
      • use of spermicidal in vagina
      • IUCD
    • 59. Female Contraception
      • Oral
      • Combined pill
      • Sequential pill
      • Phased regimen
      • Mini pill
      • Post-coital pill
      • Injectable
      • Long acting
        • progesterone alone
      • Long acting
        • progesterone + estrogen
      • Implants:
        • Norplant
    • 60. History
      • The oral contraceptive pill (combined OC) was first introduced in 1960
      • 1970: Introduction low dose or second generation of OCS
      • 1980: biphasic or triphasic regimens
      • 1990: 3rd generation OCS
      • (O + P has less androgenic activity,
      • e.g, norgestimate 0.25mg or desogestrel 0.15 mg)
      • Since then it has undergone many modifications and has been used by millions of women worldwide.
    • 61. Combined Pill
      • Low-dose oral contraceptives: products containing less than 50ug ethinyl estradiol
      • First generation oral contraceptives: products containing 50ug or more of ethinyl estradiol
      • Second generation oral contraceptives: products containing levonorgestrel, norgestimate and other members of northindrone family and 30 or 40ug ethinyl estradiol
      • Third generation oral contraceptives: products containing desogestrel or gestodene with 20 or 30ug ethinyl estradiol
        • Newer progestins (gestodene and desogestrel) have been shown to have little or no androgenic activity
    • 62. Formulations
      • Formulations may be :
      • Monophasic (each tablet contains a fixed amount of estrogen and progestin);
      • Biphasic (each tablet contains a fixed amount of estrogen, while the amount of progestin increases in the second half of the cycle); or
      • Triphasic (the amount of estrogen may be fixed or variable, while the amount of progestin increases in 3 equal phases).
    • 63. Formulations
      • Biphasic and triphasic formulations were initially developed with the intent of lowering the total steroid content of combined OCs (estrogen – 30 to 40 mcg)
      • Two types of estrogen are used in combined OCs: ethinyl estradiol and mestranol
      • Mestranol is a “prodrug” that is converted in vivo to ethinyl estradiol
      • Several different progestins, of varying degrees of progestational potency, are used in combined OCs
    • 64. Phased Regimens: Examples
      • Biphasic:
      • 10 (O+P) + 11 (O+PP) + 7 (DF)
      • Triphasic:
      • I 6 (E.O 30 µg + Levonorg. 50 µg)
      • II 5 (E.O 40 µg + Levonorg. 75 µg)
      • III 10 (E.O 30 µg + Levonorg. 125 µg)
      • Combined preparations:
      • 21 days (O+P) + 7 days (DF)
      • 99 – 100% effective
    • 65. Minipill
      • Progesterone only pill
      • To eliminate estrogen to avoid long term risks of estrogen
      • Low dose estrogen is taken daily without gap
      • Efficacy is 96-98%
    • 66. Postcoital (Emergency)
      • Levonorgestrel 0.5 mg + EE 0.1 mg – ovral tablet
      • Levonorgestrel (0.75 mg) alone – 12 Hr apart
      • Mifepristone – 400 mg (2 tablets)
    • 67. Injectable
      • Long acting Progestin alone
        • Depot medroxyprogesterone (DMPA) – 150 mg (1 ml vial) – half life – 50 days)
        • Norethidrone (Norethisterone) – 200 mg (1 ml vial) – repeat at 2 months
      • Long acting progestin + estrogen:
        • Medroxyprogesterone + estradol cypionate – IM injection – monthly
      • Implants – norplants, progestesert etc.
    • 68. Missed Pill Advise
      • If 1 or 2 of 30-35mcg ethinylestradiol pill or 1 of 20 mcg
        • Advise to take the most recent pill as soon as remembers, continue taking remaining pill at usual time, she does not require additional contraception or emergency contraception
      • If 3 or more of 30-35 or 2 or more 20 mcg
        • Advise as above, but to use extra method of contraception until pills have been taken for 7 days in a row
        • If pill is missed in week 1 ( days1-7)and unprotected sexual intercourse has taken place in pill free week or wk 1 then emergency contraception is needed
        • 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 interval
        • If one has missed > 7 consecutive days then consider as stopped COCP
    • 69. Mechanism of action
      • Combination pill, given daily for 3 of every 4 weeks:
        • Prevents ovulation by inhibiting gonadotropin secretion via effect on both pituitary and hypothalamic centers
        • Progestational agent in pill ; suppresses LH secretion(thus prevents ovulation)
        • Estrogenic agent ; suppresses FSH secretion (thus prevents selection and emergence of dominant follicle)
        • Progestin only preparations – suppresses LH surge and also by direct action
    • 70. Mechanism of action – contd.
      • Thick Cervical mucus secretion making hostile for sperm penetration
      • Failure of implantation – hyperproliferative and hypersecretory endometrium
      • Uterine and tubal contraction – peristalsis within the fallopian tube
      • Dislodging of implanted blastocyte
    • 71. Adverse Effects
      • Some combined OC users will experience minor side-effects, most commonly during the first 3 cycles.
      • These side-effects may lead to discontinuation of the combined OC
      • The most common reason patients discontinue combined OC use is:
      • Abnormal menstrual bleeding, followed by :
      • Nausea,
      • Weight gain,
      • Mood changes,
      • Breast tenderness
      • Headache.
    • 72. Adverse Effects - Late
      • Chloasma
      • Pruritus vulvae
      • Carbohydrate intolerance
      • Mood swings
    • 73. Serious Complications
      • Leg vein and pulmonary thrombosis
      • Coronary and cerebral thrombosis
      • Hypertension
      • Genital carcinoma
      • Benign hepatomas
      • Gallstones
    • 74. Contraindications (WHO)
      • < 6 weeks postpartum if breastfeeding
      • Smoker over the age of 35 (≥ 15 cigarettes per day)
      • Hypertension (systolic ≥ 160mm Hg or diastolic ≥ 100mm Hg)
      • Current or past history of venous thromboembolism (VTE)
      • Ischemic heart disease
      • History of cerebrovascular accident
      • Complicated valvular heart disease
      • Migraine headache
      • Breast cancer (current)
      • Diabetes with retinopathy/nephropathy/neuropathy
      • Cirrhosis
      • Liver tumour (adenoma or hepatoma)
    • 75. Relative Contraindications
      • Smoker over the age of 35 (< 15 cigarettes per day)
      • Adequately controlled hypertension
      • Hypertension (systolic 140–159mm Hg, diastolic 90–99mm Hg)
      • Migraine headache over the age of 35
      • Currently symptomatic gallbladder disease
      • History of combined OC-related cholestasis
      • Mentally ill
      • Undiagnosed vaginal Bleeding
      • Centchroman and male contraceptive
    • 76. Thank You
      • Points to Study:
        • Pharmacological actions of testosterone, mechanism of action, adverse effects and therapeutic uses
        • Danazol, Flutamide and Finasteride details
        • Anabolic Steroids
        • Actions of Oestrogens and uses
        • Clomiphene citrate in detail
        • Antiprogestin – Mifepristone
        • Different contraceptive measure
        • Different Hormonal contraceptives
        • Mechanism of action, adverse effects and contraindications of OCPs