1 / 81

GONADAL DRUGS

GONADAL DRUGS. Ma. Janetth B. Serrano, M.D., DPBA. Gonads: Ovary. Quiescent during rapid growth & maturation At puberty: - Gonadarche → beginning of ovarian function - Menstrual cycle → a 30- to 40- year period of cyclic function → manifested as regular episodes of bleeding

satya
Download Presentation

GONADAL DRUGS

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. GONADAL DRUGS Ma. Janetth B. Serrano, M.D., DPBA

  2. Gonads: Ovary • Quiescent during rapid growth & maturation • At puberty: - Gonadarche→ beginning of ovarian function - Menstrual cycle → a 30- to 40- year period of cyclic function → manifested as regular episodes of bleeding - Menopause → if ovaries fail to respond to gonadotropins secreted by the ant. pituitary.

  3. Gonads: Ovary Hypothalamus↓ GnRH ↓ Anterior Pituitary↓ FSH / LH↓ Ovary / Testes Estrogen/ Testosterone/ Progestins Androgens NEUROENDOCRINE CONTROL OF THE MENSTRUAL CYCLE (-) (-)

  4. Gonads: Ovary • DISTURBANCES IN OVARIAN FUNCTION: • environmental or emotional stress • anovulatory cycles: • eating disorders (bulimia,anorexia) • severe exercise • organic causes: • pituitary prolactinomas • ovary gives rise to: • androgen producing neoplasms (arrhenoblastoma, Leydig cell tumors, estrogen producing granulosa cell tumors) • minor causes: inflammatory or neoplastic processes that inluence function of the ovaries, uterus or pituitary

  5. Estrogens • Naturally occuring: • 17β – estradiol (most potent) • Estrone • Estriol

  6. Estrogens • Immediate precursors: Androstenedione / Testosterone • Ovaries – principal source of circulating estrogen • Other sources: • liver (estrone, estriol fr. estrsdiol) • Peripheral tissues (fr. androstenedione & other androgens) • Pregnancy: fetoplacental unit ( fetal adrenal zone, secreting androgen precursor, placenta) • Stallion – equilenin and equilin • Soybeans - flavinoids

  7. Estrogens PHARMACOKINETICS • binds strongly to SHBG and less to albumin • estrdiol converted by the liver to: • estrone & estriol • 2-hydroxylated derivatives • conjugated metabolites catechol estrogens • may serve as neurotransmitters in the CNS • converted by COM-T to 2- and 4- methoxy compounds • excreted in the bile; small amounts in breastmilk

  8. Biosynthetic Pathway for Estrogens: Dehydroepi- 16 α-OHase 16α-Hydroxyde- 16α-Hydroxydehy - androsterone hydroepiandros hydroepiandros- terone terone Androstenedione aromatase Estrone Estriol TESTOSTERONE aromatase ESTRADIOL

  9. Estrogens MECHANISM OF ACTION • primarily by regulating gene expression • SHBG-bound estrogens  dissociate & enter cell  bind to their receptor • Receptor-hormone complex  bind to Estrogen Response Elements or ERE’s (specific sequence of nucleotides)

  10. Estrogens PHYSIOLOGIC EFFECTS 1. Female maturation • required for 2 O sexual characteristics: • stimulate development of vagina, uterus & tubes • breast development  stromal development, ductal growth and accretion of fat • accelerated growth phase and closure of epiphysis • axillary and pubic hair • regional pigmentation of axilla, areola & genital area

  11. Estrogens PHYSIOLOGIC EFFECTS 2. Endometrial effects • hyperplasia of the endometrium  continuous exposure 3. Metabolic and Cardiovascular effects: • Lipoprotein:  HDL , slight  LDL •  plasma cholesterol •  plasma triglycerides 4. Blood Coagulation • enhance coagulability •  Factors II, Vii, IX, X •  antithrombin III •  plasminogen level  platelet adhesiveness

  12. Estrogens CLINICAL USES • Primary hypogonadism • associated with hypopituitarism • Turner’s syndrome – ovarian dysgenesis with dwarfism • treatment begins at puberty – 11 to 13 years: • to stimulate development of 2O sexual characteristics and menses • to prevent osteoporosis • to avoid physiologic consequenses of delayed puberty and estrogen deficiency • Dosage: Conjugated estrogen 0.3 mg or Ethinyl estradiol 5-10ug • on days 1 to 21 of each month • when growth is completed  Chronic Tp with estrogen and progestins

  13. Estrogens CLINICAL USES 2. Postmenopausal Hormone Replacement Therapy • major indication • prevent bone loss (osteoporosis) • decrease vasomotor symptoms • prevention of cardiovascular disease • prevent vaginitis • Dosage: Conjugated Estrogen – 0.3 to 1.25 ug/day Ethinyl Estradiol – 0.01 to 0.02 mg/day

  14. Estrogens CLINICAL USES • Replacement Regimen: A: Sequential hormone administration 1. Estrogen for first 25 days 2. MPA (Medroxyprogesterone acetate) 10 mg/day for the last 10 to 14 days of estrogen therapy 3. No hormone treatment for 5 to 6 days (+) withdrawal bleeding B: “Continuous” hormone administration 1. estrogen 0.625 mg given continuously on a daily basis 2. progestin MPA 2.5 to 5 mg jointly given during the first 10 to 13 days of each month 3. no cyclic bleeding • PROGESTINS – included to decrease endometrial hyperplasia and incidence of endometrial carcinoma

  15. Estrogens CLINICAL USES 3. Contraception • major indication 4. OTHER USES: • DUB & intractable dysmenorrhea (Es + Progestins) • Hirsutism & amenorrhea • DES  prostate carcinoma • Severe cystic acne

  16. Estrogens ADVERSE EFFECTS • postmenopausal bleeding • carcinogenic action – breast, endometrial • thromboembolic disease, HPN • GB disease, cholestasis • Nausea & breast tenderness • Migraines • Changes in mood

  17. Estrogens CONTRAINDICATIONS • CONTRAINDICATIONS: • estrogen- dependent neoplasms • undiagnosed genital bleeding • history of liver disease • history of thromboembolic disorder • heavy smokers

  18. Gonadal Inhibitors Anti - Estrogens ANTI-ESTROGENS: A. Tamoxifen • a competetive partial agonist inhibitor of estradiol at estrogen receptors • nonsteroidal agent given orally • initial half-life: 7 to 14 hours • excretion: liver • Cl. Indication: palliative/adjuvant tp of breast CA • Dosage: 10-20 mg BID orally • Adverse effects: nausea & vomiting • hot flashes • vaginal bleeding, menstrual irregularities, skin rash •  risk of endometrial cancer •  loss of lumbar spine bone density • plasma lipid changes  risk of atherosclerosis

  19. Gonadal Inhibitors Anti - Estrogens B. TOREMIFENE C. RALOXIFENE • “selective estrogen receptor modulator” • high first pass effect, large Vd • long half-life: >24 hours • Cl. Indication: prevention of postmenopausal osteoporosis D. CLOMIPHENE • competetive inhibitor of endogenous estrogen • partial agonist at pituitary • ovulation-inducing agent

  20. Gonadal Inhibitors Anti - Estrogens ESTROGEN SYNTHESIS INHIBITORS 1. GnRH • continuous administration prevents ovarian synthesis of estrogen 2. AMINOGLUTETHIMIDE • inhibits aromatase activity 3. AROMATASE INHIBITORS a. Testolactone – weak inhibitor b. Anastrozole • selective nonsteroidal inhibitor of aromatase • effective in tamoxifen-resistant breast tumors c. Letrozole – similar to anastrozole d. Exemestane • steroid molecule that irreversibly inhibits aromatase • advanced breast CA e. Fadrozole – newer oral nonsteroidal

  21. Ovulation Inducing Agents CLOMIPHENE • Partial agonist at estrogen receptors • MOA:  secretion of gonadotropins & estrogens by inhibiting estradiol’s negative feedback effect • Effects: 1. stimulate ovulation in females with amenorrhea & other ovulatory disorders 2. blocks inhibitory influence of estrogen on the hypothalamus • Clinical Use: 1. Treatment of disorders of ovulation in patients wishing to be pregnant • no use in ovarian & pituitary failure • single ovulation induced by a single course of therapy

  22. Ovulation Inducing Agents CLOMIPHENE • Dosage: 50 mg/ d X 5 days • (+) ovulation  same course repeated until pregnancy occurs • (-) ovulation  100 mg/d X 5 days  if (+) menses & ovulation, start next course on 5th day of cycle • Adverse Effects: • hot flushes – most common • eye symptoms – due to intensification & prolongation of after images • ovarian enlargement • multiple pregnancy – 10% • rare: headache, constipation, allergic reactions, reversible hair loss • C/I: patients with enlarged ovaries • > 1 year tx: assted with low-grade ovarian CA

  23. Progestins • Natural: PROGESTERONE • most important progestin in humans • precursor to estrogens, androgens, adrenocortical steroids • synthesized in the ovary (corpus luteum), testis, adrenals, placenta

  24. Progestins • Synthetic: A. 21-Carbon compounds (Progestrone & derivatives) • Hydroxyprogesterone - longest DOA (8-14 days) • Medroxyprogesterone • Megestrol B. 17-Ethinyl testosterone derivatives • Dimethisterone

  25. Progestins C. 19-Nortestosterone derivatives (3rd generation) 1. Desogestrel 6. Norethindrone acetate 2. Norethynodrel 7. Ethynodiol acetate 3. Lynestrenol 8. L-Norgestrel 4. Norethindrone 9. Gestodene 5. Norgestimate • MECHANISM: • binds to progesterone receptors

  26. Progestins PHYSIOLOGIC EFFECTS • Carbohydrate metabolism •  insulin levels •  insulin response to glucose • promote glycogen storage in the liver • favor fat deposition • promote ketogenesis • compete with aldosterone • ( Na+ reabsorption)

  27. Progestins PHYSIOLOGIC EFFECTS •  body temperature •  ventilatory response to CO2 • depressant & hypnotic effects • Sexual characteristics: • breast: alveolobular devt. of the secretory apparatus • endometrium: maturation & secretory changes • Important in the maintenance of pregnancy •  plasma amino acid levels  urinary nitrogen excretion

  28. Progestins Synthetic progestins: • no androgenic activity: • desogestrel, • norgestimate, • gestodene

  29. Progestins PHARMACOKINETICS • rapidly absorbed • approx. half life: 5 min • stored in body fats • metabolite: Pregnanediol • Elimination: urine as Pregnanediol glucoronate

  30. Progestins CLINICAL USES • Hormone replacement therapy • Hormonal contraception • Ovarian suppression: > dysmenorrhea > hirsutism • endometriosis > uterine bleeding • Premenstrual syndrome • progesterone & MPAProgestins

  31. Progestins CLINICAL USES • Diagnostic test Estrogen secretion • Progesterone 150 mg/d or MPA 10 mg/d for 5-7 days  withdrawal bleeding in amenorrheic patients • Single drug: • MPA 150 mg IM every 90 days  prolonged anovulation and amenorrhea • MPA 10-20 mg p.o. twice weekly or 100 mg/m2 I.M. every 1-2 weeks  prevent menstruation

  32. Progestins ADVERSE EFFECTS •  BP •  HDL  androgenic progestins

  33. Other Ovarian Hormones 1. ANDROGENS • testosterone, androstenedione, dehydroepiandrosterone • responsible for hair growth, stimulation of libido, metabolic effects • asstd. with hirsutism & amenorrhea 2. INHIBIN and ACTIVIN •  dimer (inhibin)  inhibits FSH secretion •  dimer (activin)  FSH secretion

  34. Other Ovarian Hormones 3. RELAXIN • found in the ovary, placenta, uterus •  glycogen storage and water uptake • facilitates dilatation & shortens labor 4. Non steroidal substances • corticotropin-releasing hormone, follistatin, PG • with paracrine effects within the ovary

  35. Gonadal Inhibitors Anti - Progestins 1. MIFEPRISTONE (RU486) • a derivative of ‘19-nor progestin norethindrone’ • a potent competetive antagonist of progesterone and glucocorticoid at their receptors • acts as partial agonist if progestin is absent • (+) luteolytic in women at midluteal period • Pharmacokinetics: • oral route with good bioavailability • plasma half-life: 20 to 40 hours • hepatic metabolism • elimination: feces

  36. Gonadal Inhibitors Anti - Progestins MIFEPRISTONE • Therapeutic indications: 1. Medical abortion during the first trimester • dosage: 400-600mg/day X 4 days or 800 mg/day X 2 days + Prostaglandin 48 hrs after antiprogestin to  myometrial contraction & ensure expulsion of detached blastocyst • major adverse effect: prolonged bleeding • combination: 600 mg o.d. SD + PG E1 vaginal pessary or 1 gm. Misoprostol (95% effective during 1st 7 weeks post conception) • adverse effects: vomiting, diarrhea, abdominal pain, pelvic pain

  37. Gonadal Inhibitors Anti - Progestins MIFEPRISTONE Therapeutic indications: 2. Postcoital contraceptive • prevents implantation • dosage: 600 mg SD 3. Induction of labor after fetal death & at the end of 3rd trimester 4. Tx of endometriosis, leiomyoma, breast cancer, meningiomas

  38. Gonadal Inhibitors Anti - Progestins DANAZOL • an isoxazole derivative of ethisterone • weak agonist at progestational, androgenic and glucocorticoid receptors • inhibitor of gonadal function • MOA: binds to receptors  initiate androgen-specific RNA synthesis • Major metabnolite: ETHISTERONE –with progestational & androgenic effects • t ½ = >15 hrs • Elimination: urine & feces

  39. Gonadal Inhibitors Anti - Progestins DANAZOL Clinical Uses: • treatment of endometriosis • 600 mg/d reduced to 400 mg/d after 1 mo. then 200 mg/d after 2 mos (85% with improvement in 3-12 mos) • fibrocystic disease of the breast • hematologic or allergic disorders: • hemophilia, Christmas disease, ITP, angioneurotic edema

  40. Gonadal Inhibitors Anti - Progestins DANAZOL Major adverse effects: • weight gain, edema,  breast size, acne & oily skin,  hair growth, headache, deepening of voice, hot flushes, muscle cramps • Caution: hepatocellular damage • C/I: pregnancy & lactation  urogenital abnormalities

  41. Gonads: Testis • both gametogenic & endocrine functions • Anterior Pituitary FSH (+) (-) (-) LH TESTOSTERONE Activin Inhibin Sertoli cells Mullerian Inhibitory factor ESTRADIOL LEYDIG CELLS SEMINIFEROUS TUBULES

  42. Testosterone TESTOSTERONE • most important androgen secreted by the testes • 8 mg/day produced daily • 95% by Leydig cells; 5% by androgens • Plasma levels: • 0.6 ug/dL after puberty • (declines after 50 years of age) • 0.03 ug/dL = females

  43. Gonads: Testis HYPOTHALAMUS GnRH Anterior Pituitary LH Testes Ketoconazole Spirinolactone TESTOSTERONE 5α - Reductase FINASTERIDE Dihydrotestosterone Androgen Receptor Complex Flutamide Cyproterone Spirinolactone Androgen Response Element Expression of Appropriate genes in androgen-responsive cells

  44. Gonads: Testis Other androgens/hormones produced: • dihydrotestosterone • androstenedione • dehydroepiandrosterone • pregnenolone • progesterone & 17-hydroxylated derivatives

  45. Testosterone • BINDING: 65% - SHBG 2% - free 33% - albumin • METABOLISM: Testosterone converted to dihydrotestosterone (major active androgen) by 5--reductase

  46. Testosterone PHYSIOLOGIC EFFECTS: A. Changes during puberty(Adrenarche) • testosterone & 5 dihydrotestosterone  penile & scrotal growth • skin  pubic, axillary & beard hair (Androstenedione, DHEA)  more active sebaceous glands  thicker & oilier skin • larynx  vocal cords thicker  low pitch voice • skeletal growth

  47. Testosterone PHYSIOLOGIC EFFECTS: B. increase lean body mass C. male development (2O sexual characteristics) • stimulate development & maturation of sperm • stimulate development of the epididymis, vas deferens, seminal vesicles, scrotum, penis, prostate D. anabolic effect on muscle & bone mass • increase protein synthesis, decrease protein breakdown • measured by  urine nitrogen secretion

  48. Testosterone PHYSIOLOGIC CHANGES E. musculinization in females F. metabolic effects: •  hormone binding •  liver synthesis of clotting factors, triglyceride, lipase,  anti-trypsin •  HDL • stimulate renal erythropoietin secretion

  49. Testosterone PREPARATIONS: Natural androgen:testosterone Synthetic: Parenteral: ~ testosterone proprionate ~ testosterone enanthate ~ testosterone cypionate Oral: ~ Danazol ~ Fluoxymesterone ~ Methyltestosterone Anabolic steroids: ~ Oxandrolone ~ Stanozolol

  50. Testosterone CLINICAL USES: 1. Androgen replacement therapy in men • hypogonadism • pituitary deficiency • given at puberty  growth spurt & 2O sexual characteristics • Dosage: Testosterone enanthrate • 50 mg IM q 4 wks; then q 3 wks; then q 2 wks (@ change at 3 mos interval) • double dosage at 100 mg q 2 wks until maturation is complete  then adult dose of 200 mg q 2 wks

More Related