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Gonadal hormones and inhibitors

Gonadal hormones and inhibitors






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    Gonadal hormones and inhibitors Gonadal hormones and inhibitors Presentation Transcript

    • Gonadal Hormones and Inhibitors
      Ma. Victoria Matias-Villarica, M.D.
      Dept. of Pharmacology
      Fatima College of Medicine
    • Objectives:
      Review gonadal hormone secretion and their functions
      Identify the uses of these hormones
    • Estrogen
      Natural Estrogen
      a. 17-β-estradiol
      b. Estrone
      c. Estriol
      Synthetic Estrogen
      a. Ethinyl estradiol
      b. Quinestrol
      c. Mestranol
    • Estrogen (cont.)
      Non-steroidal Synthetic Estrogen
      a. Methestrol
      b. Dienestrol
      c. Benzestrol
      d. Hexistrol
      e. Diethylstilbestrol
      f. Chlorotrianisene
      g. Methallenestril
      a. Tamoxifen
      b. Clomiphene
    • Progesterone
      Natural Progestin
      - Progesterone
      Synthetic Progestin
      a. Norgestrol
      b. Medroxyprogesterone
      c. Norethindrone
      a. Danazol
      b. Mifepristone
    • Androgens
      Natural Androgen
      - Testosterone
      Synthetic Androgen
      a. Methyltestosterone
      b. Fluoxymesterone
      Anabolic Steroid
      a. Oxandrolone
      b. Stanozolol
    • Androgens (cont.)
      Androgen Antagonist
      a. Finasteride
      b. Flutamide
      c. Cyproterone
      d. Ketoconazole
      e. Spirinolactone
    • Ovary
      - Quiescent
      - Gonadarche
      - Menarche
      - Menopause
      - Disturbances of ovarian function:
      a. emotional and environmental stress
      b. anovulatory cycles
      c. organic causes – pituitary adenomas, arrhenoblastoma, Leydig cell tumors
    • Estrogen:
      Secreted by the theca cells, corpus luteum, placenta and adrenals and testes
      Intracellular receptors for lipid soluble agents
      Bounded by SHBG
      Metabolites: cathecol estrogen -> neurotransmitters -> converted to 2- and 4-methoxycompounds by COMT
      Enterohepatic circulation
    • Estrogen: Physiologic effects
      Female maturation
      - stimulate the development of vagina, uterus, uterine tubes
      - breast: stromal development, ductal development
      - growth: accelerated; closure of epiphysis of long bones
      - growth of axillary/pubic hair
      - typical female body contour
    • Estrogen: Physiologic effects (cont.)
      on sexual organs (primary and secondary sexual characteristics)
      ovaries : stimulate follicular growth; small doses cause an increase in weight of ovary; large doses cause atrophy
      uterus: endometrial growth
      vagina: cornification of epithelial cells with thickening and stratification of epithelium
      cervix: increase of cervical mucous with a lowered viscosity (favoring sperm access)
    • Estrogen: physiologic effects (cont)
      Endometrial effects – hyperplasia with abnormal bleeding patterns
      Cardiovascular effects:
      - ↑HDL, ↓LDL; ↓antithrombin III; ↑ Fx II, VII, IX, X; ↑plasminogen levels, ↓platelet adhesiveness
    • Estrogen: physiologic effects (cont)
      Other effects:
      - influence behavior and libido
      - loss of fluid from intravascular into the extravascular space (edema)
      - induce synthesis of progesterone receptors
      - electrolytes: retention of Na+, Cl- and water by the kidney
      - cholesterol: hypocholesterolemic effect
      - skin:increase in vascularization, development of soft, textured and smooth skin
      - bone:increase osteoblastic activity
    • Estrogen: Clinical uses
      Post-menopausal hormonal therapy
      -reduction of MI (50%), fatal strokes (40%)
      -prevent fractures
      -0.3mg D1-D21 monthly + medroxyprogesterone acetate
      -S/P hysterectomy – 5 days/week
      -atrophic vaginitis - topical
      Oral contraceptives
      Hypogonadism – 0.3mg D1-D21 monthly
      Prostate Ca
    • Natural estrogens
      Conjugated estrogenic substances:
      an amorphous preparation containing water soluble conjugated forms of mixed estrogens from the urine of pregnant mares (Premarin, Cenestin - synthetic conjugated estrogens)
      estradiol :
      oral : Estrace
      transdermal: Climara, Alora, Vivelle, Vivelle-Dot, Estraderm, FemPatch
    • Natural estrogens
      Kestrone 5 (injectable only)
      esterified estrogen
      (75-85% sodium estrone sulfate and 6- 15% sodium equilin sulfate)
      Estratab; Menest
      estropipate (piperazine estrone sulfate)
      Ogen; Ortho-Est
    • Natural estrogens
      Sustained-release injectables:
      estradiol valerate in oil (Delestrogen; Valergen)
      estradiol cypionate in oil (depGynogen; DepoGen)
      duration of action from 3 to 8 weeks
      esterified at C-17 hydroyl group
    • Estrogen products
    • Estrogen: Contraindications
      Estrogen dependent neoplasm (breast, endometrium)
      Undiagnosed genital bleeding
      History of thromboembolic disorders
      Pregnant women
    • Progesterone:
      Synthesized in the ovary, testes, adrenals
      Produced primarily by corpus luteum
      Males: 1-5mg daily or 0.03ug/dl plasma level
      Kinetics: rapidly absorbes; t1/2 – 5mins; completely metabolized in the liver
      Natural hormone secreted
      by the corpus luteum and the
      placenta ( a C-21 steroid)
      it is also an important intermediate in steroid biogenesis in all tissues that produce steroids (testes, adrenal cortex)
      Intestinal absorption is quite erratic; must be micronized for
      most effective absorption (Prometrium)
    • Progesterone: Physiologic effects:
      Affects carbohydrate metabolism
      Compete with aldosterone
      ↑ body temperature
      Breast: alveolobular development of the secretory apparatus of the breast
      Endometrium: maturation and secretory changes
      ↓plasma levels of amino acids
    • Progesterone: Clinical uses
      Hormonal replacement therapy
      Diagnosis: estrogen secretion
    • Progesterone: CI/AE
      Increase BP
      Decrease plasma HDL
    • Other androgens secreted by the ovary:
      DHEA (dehydroepiandrosterone)
    • Testes:
      Functions: sperm production (FSH)
      testosterone synthesis (LH)
      8mg testosterone daily
      Weak androgen: androstenedione, dehydroepiandrosterone
      Active androgen: dihydrotestosterone
      Testosterone is converted to estradiol by p450 aromatase
    • Natural androgens
    • Testosterone: Physiologic effect
      Changes in the skin (pubic, axillary, beard)
      Skeletal growth
      ↑lean body mass
      Male development
      Anabolic effect on muscle and bone mass: ↑ CHON synthesis, ↓ CHON breakdown
      Other effects: erythrocyte production, musculinization in females
    • Testosterone: Clinical Uses
      Androgen replacement therapy
      Gynecologic disorders
      Protein anabolic agent
      Refractory anemia
      Growth stimulators
      Abused in sports
      “Slows” aging
    • Other Uses for Androgens
      Replacement therapy in hypogonadism
      delayed puberty
      metastatic breast cancer in women
      postpartum breast pain/engorgement
      male climacteric
    • Testosterone: Contraindication
      Pregnant women
      Ca of the prostate, breast
      Adverse effect:
      Musculinizing effect in women
      Alteration of serum lipid profile
      Hepatocellular Ca
    • Testosterone products
      testosterone in aqueous suspension (short-acting)
      testosterone propionate in oil
      testosterone enanthate in oil (Delatestryl)
      testosterone cypionate in oil (Depotest)
      testosterone pellets (Testopel)
      testosterone transdermal system (Androderm)
    • Anti-Estrogen
      - partial agonist at estrogen receptors
      - act as competitive inhibitors
      - stimulates ovulation by preventing feedback inhibition
      - AE: hot flashes, eye symptoms, ovarian cyst, skin rxn, multiple births
      - 50mg OD x 5days; 100mg OD x 5days; 100mg OD x 5days
    • Anti-Estrogen:
      - Act as competitive inhibitor
      - For breast Ca
      - AE: hot flashes, N and V, vulvar pruritus, menstrual irregularities
      - 10-20mg BID (35% ↓ but not >5yrs)
      □ Toremifene – prevent bone loss, ↓atherosclerosis; (+) uterus
      □ Raloxifene - prevent bone loss, ↓atherosclerosis; (-) uterus
      aromatase is a cytochrome P450 enzyme that catalyzes the conversion of adrenal androgen androstenedione to estrone in both pre- amd post menopausal women
      reaction occurs in the liver, muscle, adipose and breast tissue
      in post-menopausal women, aromatization is responsible for the majority of circulating estrogen
      aminoglutethimide was used but has now been replaced by more selective drugs
      drugs may be steroidal (testolactone, emestane) or non-steroidal (anastrozole, letrozole)
      estrogen deprivation through aromatase inhibition is an effective and selective treatment for some post-menopausal patients with hormone-dependent breast cancer
      both of these drugs are used in the treatment of advanced
      breast cancer in post-menopausal women with disease
      progression following tamoxifen therapy
    • Exemestane (Aromasin)
      structurally related to androstenedione
      acts as an irreversible (suicide) inhibitor of aromatase
      has no effect on other enzymes involved in steroidogenesis
      indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy
    • Anti-Progestin
      Mifepristone – RU 486
      - inhibits activity of progesterone
      - post-coital contraceptive (600mg SD), abortifacient (400-600mg x 4days/ 800mg/day x 2days (85%) or 600mg SD + misoprostol 1mg (95% 7wks); Cushing’s syndrome
      - AE: heavy bleeding, N and V, anorexia, abd. pain
    • Anti-Progestin
      - suppress ovarian function; inhibits mid-cycle surge of LH, FSH
      - endometriosis (600mg/d)
      - fibrocystic dis. of the breast
      - AE: weight gain, edema, acne, cramps
      - CI: pregnancy, breastfeeding
    • Anti-Androgen
      Finasteride– inhibits 5-α – reductase (5mg/d)
      - BPH(5mg/D), baldness (1mg/D)
      Spirinolactone- ↓synthesis of testosterone on the testes
      Ketoconazole - ↓synthesis of testosterone on the testes
      - inhibits binding to androgen receptor
      Cyproterone– inhibits binding to androgen receptor
      - hirsutism in women, prostatic Ca
      Flutamide– inhibits binding to androgen receptor
      - prostatic Ca
      1. Bicalutamide (150-200mg/d)
      2. Nilutamide (300mg/d x 3 days)
    • Antiandrogen drugs
    • Finasteride : Proscar and Propecia
    • Hormonal Contraceptives
      Combination oral contraceptive
      I. Monophasic – provide constant amount of estrogen and progesterone (21day)
      II. Biphasic – provide varying amount of progestin but constant amount of estrogen
      III. Triphasic -provide varying amounts of estrogen and progestin
      Transdermal combination contraceptive
    • Examples of Oral Contraceptives
      4 types:
      monophasic: Loestrin, Levlen, Levora, Levlite, Desogen, Lo/Ovral, Ortho-Cept, Nordette, Demulen, Ovcon, Modicon, Zovia, Loestrin, Apri, Microgestin, Yasmin, Ortho-Cept, Levora, Alesse
      biphasic: Ortho-Novum 10/11, Nelova 10/11, Necon 10/11, Jenest-28, Mircette
      triphasic: Ortho-Novum 7/7/7, Tri-Norinyl, Tri-Levlen, Triphasil, Trivora-28, Estrostep
      progestin-only: Micronor, Nor-QD, Ovrette
    • Adverse effect of combination oral contraceptive:
      Mild:nausea, mastalgia, breakthrough bleeding, changes in serum protein, transient headache, withdrawal bleeding
      Moderate:breakthrough bleeding, weight gain, skin pigmentation, acne, hirsutism, vaginal infections, amenorrhea
      Severe:vascular disorders (MI, CVA), cholestatic jaundice, depression, Ca
    • Hormonal Contraceptive
      Progesterone only contraceptive
      Oral: Norethindrone, Norgestrel
      Subdermal: Norgestrol, Norplant
      Injectable: Medroxyprogesterone Acetate/ Depoprovera
      Post-coital contraceptive
      Levonorgestrel implants (Norplant system)
      intrauterine progesterone contraceptive system (Progestasert)
      medroxyprogesterone contraceptive injection (Depo-Provera)
      nonoxynol contraceptive creams and gels
    • Emergency contraceptives
      drugs used for the prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure
      to be effective these must be taken within 72 hours of intercourse
      two products are available:
      Plan B: 0.75 mg levonorgestrel
      Preven: 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol (this product includes a pregnancy test kit)
    • Male Contraceptive
      Gossypol – phenolic compound that reduces sperm density by 99% in men and impairs sperm motility
      - 20mg/D x 2 mos. or 60mg/wk
      - not continued >2yrs.
    • In summary……
      Identify gonadal hormone secretion and their functions
      Know the uses of these hormones
    • Types of steroid hormones
      Glucocorticoids; cortisol is the major representative in most mammals
      Mineralocorticoids; aldosterone being most prominent
      Androgens such as testosterone
      Estrogens, including estradiol and estrone
      Progestogens (also known a progestins) such as progesterone
    • Miscellaneous topics
    • Performance Enhancing Drugs
      1995 poll – 198 Olympic level power athletes
      • Given the ffng scenario, you are offered a banned substance with 2 guarantees:
      1. you will not be caught
      2. by taking the substance you will win your event
      • Only 3 said NO
    • Same poll, new scenario:
      1. the substance will allow you to win every competition you enter over the next 5 years
      2. however, the substance will kill you
      More than 50% would still use the substance!
    • Anabolic, androgenic, and growth hormones
      Anabolicrefers to muscle building (Testosterone, Dianobol, and Deca Durabolin)
      Androgenic refers to increased masculine characterictics (Equipoise, Masteron, and Trenbolone)
      (2005,march NIDA Infofacts)
      Growth hormones are different in nature from anabolic-androgenic steroids.
      (2005,march NIDA Infofacts)
    • Georgia Bureau of Investigation at 2:30 p.m. EDT on July 17, 2007
      There are four bills pertaining to reproductive health and/or population management that have been filed for deliberation in both the House of Representatives and the Senate for the 14th Congress. These are House Bill No. 17 authored by Rep. Edcel Lagman, House Bill No. 812 authored by Rep. Janette Garin, Senate Bill No. 40 authored by Sen. Rodolfo Biazon and Senate Bill No. 43 authored by Sen. Panfilo Lacson.
    • The bill is controversial, as it is being opposed by the Catholic Church. The Catholic Church is against the use of artificial contraceptives
      House Bill No. 17, also known as the proposed "Reproductive Health and Population Development Act of 2008," will cover the following areas:
      information and access to natural and modern family planning;
      maternal, infant and child health and nutrition;
      promotion of breast feeding;
      prevention of abortion and management of post-abortion complications;
      adolescent and youth health; prevention and management of reproductive tract infections, HIV/AIDS and sexually transmitted diseases;
      elimination of violence against women; counseling on sexuality and sexual and reproductive health;
      treatment of breast and reproductive tract cancers;
      male involvement and participation in reproductive health;
      prevention and treatment of infertility; and
      reproductive health education for the youth.
    • Finally …….
      The End
      Thank You!