Pharmacology of Estrogens and Progestins Flashcards Preview

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Flashcards in Pharmacology of Estrogens and Progestins Deck (25)
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Principal estrogens in humans

  • Estradiol (E2) > Estrone (E1) > Estriol (E3)
    • Most --> least potent
  • Estradiol: most abundant and potent estrogen in menstruating women
  • Estrone: predominant estrogen during menopause
  • Estriol: made by placenta


Estrogen-like compounds in humans

  • Phytoestrogens
    • Estrogenic and anti-estrogenic activities
    • Nonsteroidal compounds that occur naturally in many plants, fruits, and vegetables
    • 3 primary types:
      • Ligans: flaxseed, lentils, grains, fruits, veggies
      • Isoflavones (most potent of phytoestrogens): Genistein, Daidzein, soybeans, chickpeas, lentils
      • Coumetans: split peas, lima beans, pinto beans
    • Alternative to HRT, perception of improved safety
  • Bisphenol A
    • Synthetic compound found in plasticizers
    • Weak affinity but potential toxicity due to bioaccumulation in environment


Cell types in which estrogens are made

  • Premenopausal women:
    • Ovarian granulosa cells with thecal androgen contribution
  • Postmenopausal women, men: 
    • Adipose tissue (estrone synthesized from adrostenediol secreted by adrenal cortex)
    • Conversion of testosterone to estradiol via aromatase


Site of progesterone biosynthesis

  • Premenopausal women:
    • Corpus luteum
    • Adrenal cortex
    • Placenta
  • Postmenopausal women, men:
    • Testis and/or adrenal cortex


Steps of estradiol synthesis

  1. LH stimulates theca cell (adenylyl cyclase pathway) --> increases synthesis of LDL receptors and side-chain-cleavage enzyme
  2. Theca cells increase synthesis of androstenedione
  3. Androstenedione freely diffuses to granulosa cells
  4. FSH (through adenylyl cyclase pathway) --> stimulates granulosa cell to produce aromatase
  5. Aromatase converts converts androstenedione to estrone
  6. 17b-HSD converts estrone to estradiol OR 17b-HSD can convert androstenedione to testosterone, then to estradiol via aromatase
  7. Estradiol diffuses into blood vessels


Negative feedback in estrogen biosynthesis

  • Synthesis of estrogen and progesterone by ovary - under control of hypothalamic-pituitary axis
  • Estrogen synthesis regulated by negative feedback system
    • Estrogen feeds back primarily at level of pituitary to inhibit LH/FSH secretion
    • Progesterone acts at both pituitary and hypothalamic levels
  • Prior to puberty: GnRH pulse generator in arcuate nucleus of hypothalamus does not function
    • GnRH is shut down --> no menstrual cycles


MOA of estrogens

  • Unliganded estrogen receptor (ER) exists as monomer within nucleus
  • Agonists (estrogen): 
    • Bind to ER, cause conformational change to facilitate dimerization & interaction with specific estrogen response element sequences in DNA
    • Proteins: co-activators SWI/SNF, SRC-1, p300, TRAP
  • Antagonists (tamoxifen): 
    • Also bind to ER but produce different receptor conformation
    • Antagonist-induced conformation facilitates dimerization and interaction with DNA
    • Proteins: co-repressors NcoR, HDAC1


MOA of progestins

  • Cystolic receptor (A or B, induced by estrogen) translocates to nucleus, regulates gene transcription via progesterone response elements


Use of estrogen/progestin agonists and antagonists in clinic: primary, secondary, tertiary defects

  • Primary level: ovarian defect
    • Congenital: Turner's syndrome
    • Acquired: Autoimmune, chemotherapy, radiation
    • Labs: High GnRH, high LH/FSH
  • Secondary level: pituitary defect
    • Pituitary tumors: prolactinomas
    • Labs: Normal GnRH, low LH/FSH
  • Tertiary level: hypothalamic defect
    • Congenital: Kallman's syndrome
    • Acquired: Illness, stress, excessive exercise, anorexia
    • Labs: Low GnRH, low LH/FSH


Other clinical indications for estrogen/progestin agonists & antagonists 

  • Menopause
    • Administer estrogens in conjunction with calcium, vitamin D, and bisphosphonates
    • Estrogen therapy alleviates vasomotor instability, emotional lability, sleep disturbances, atrophy of estrogen-dependent tissues, and osteoporosis
    • Lack of estrogen precipitates most menopausal symptoms
  • Primary ovarian deficiency
    • Estrogen levels 1/8 of normal, progesterone levels 1/3 of normal, elevated LH/FSH
  • Contraception
    • Estrogens used in conjunction with progestin to inhibit production of LH/FSH and GnRH; prevent ovulation
  • PCOS
    • Tx with contraceptives to block androgen production in combination with anti-androgen (e.g. spironolactone)
  • HRT
    • Progestins used with estrogens when uterus is intact
  • Ovarian suppression --> progestin
    • Dysmenorrhea
    • Endometriosis
    • Uterine bleeding


Estrogen preparations

  • 17-b-estradiol (E2)
    • Oral (micronized), transdermal patches, vaginal cream, and vaginal ring
  • Esters of 17-b-estradiol (EE)
    • Oral, IM
  • Synthetic conjugated estrogens (estrone sulfate)
    • Oral
  • Conjugated equine estrogens (CEE) (Premarin)
    • Oral (~0.625 mg/day); HRT
  • Ethinyl estradiol
    • Oral (20-35 ug/day); birth control pill


Progestin preparations

  • Progesterone
    • Micronized oral form (Prometrium), injectable oil-based solution, vaginal cream, IUD
  • Esters of progesterone
    • Medroxyprogesterone acetate - orally (Provera) or IM administration (Depo-Provera)
  • 19-nortestosterone derivatives
    • Norethindrone, norgestrel - oral with estrogen for contraception 
    • Norgestrel also given as subdermal implant (Norplant)
    • Estronorgestrol released with ethinyl estradiol (Nuvaring)
    • Norelgestromin and ethinyl estradiol released transdermally (Evra patch); superior compliance to OCPs


Estrogen/progestins pharmacology

  • Adding ester group increases lipid solubility and half-life
  • Adding ethinyl group dereases hepatic degradation
  • Differ in potency, but very little in efficacy
  • Oral route impacts liver, increasing hepatic production of thyroxine-binding globulin, corticosteroid-binding globulin, sex hormone binding globulin, triglycerides, HDL cholesterol, and clotting factors
  • Transdermal estrogen administration only minimally increases hepatic-produced entities
    • Prevention of bone density loss 
    • Treatment of menopausal symptoms
    • Lower risk of venous thrombosis and stroke
    • Less effect on serum lipid concentrations


Aromatase inhibitors

  • Anastrozole (arimidex) and letrozole (femara)
    • Non-steroidal, competitive
  • Exemestane (aromasin) and formestane (lentarin)
    • Steroidal, non-competitive
  • Block production of estrogens from androstenediol or testosterone


Clinical uses of aromatase inhibitors

  • Treatment of breast cancer, primarily in postmenopausal women
  • Benefits: 
    • Highly efficacious (superior to tamoxifen)
    • No stimulation of endometrium
  • Side effects:
    • Joint disorders
    • Osteoporosis
    • Hypercholesterolemia


Risks of administering estrogens/progesterones

  • Cancer (from unopposed estrogen)
  • Increased risk of stroke, heart attack, 'serious' blood clots (DVT), pulmonary embolus
  • Changes in lipid metabolism (increased triglycerides, but overall favorable effect on plasma lipoproteins)
    • Benign liver tumors
  • Gallbladder disease (stones)
  • Migraine
  • Nausea 
  • Hypertension


Benefits of administering estrogens/progesterones

  • Decreased risk of:
    • Ovarian cancer
    • Endometrial cancer
    • Ovarian retention cysts
    • Ectopic pregnancy
    • Pelvic inflammatory disease
    • Benign breast disease
    • Osteoporosis


Selective estrogen receptor modulators (SERMs)

  • Display agonistic or antagonistic activities depending on tissue and endpoint
  • Estrogen targets:
    • Breast (promotes cancer)
    • Endometrium (promotes cancer)
    • Bone (maintain bone density, anti-resorptive)
    • Cardiovascular system (arterial dilation)
    • CNS (cognitive and neuroprotective)
    • Liver (stimulates uptake of serum lipoproteins, increases synthesis of coagulation factors)
  • Ideal SERM for hormone replacement:
    • Antagonist in endometrium and breast
    • Agonist in bone, cardiovascular system, CNS


SERMs approved for use in the US

  • Prototypes: 
    • Tamoxifen (Nolvadex)
    • Raloxifene (Evista)
    • Toremiphene (Fareston)
    • Clomiphene (Clomid, Serophene)
  • Tamoxifen and toremiphene are used in tx of breast cancer
    • Act as antagonist at breast but agonist in endometrium (used for < 5 years due to increased risk of endometrial cancer)
  • Raloxifene used for osteoporosis
    • Acts as a partial agonist in bone and does not stimulate endometrial proliferation
  • Clomiphene used for tx of infertility
    • Induces ovulation by antagonizing inhibitory actions of estrogens and level of pituitary
    • Partial agonist at endometrium and causes hot flashes
  • Newer: Femarelle (used for menopause symptoms and maintaining bone health), lasofoxifene, arzoxifene, bazedoxifene


Women's Health Initiative

  • 15yr study to examine effects of HRT on heart disease, fractures, breast cancer
  • 2 arms: 
    • Estrogen/progestin
    • Estrogen alone
  • Major outcomes:
    • Increased risk of breast cancer (due to oral progestin component)
    • Increase in stroke and pulmonary embolism (due to oral estrogen component; increase in clotting factors)
  • Concerns of study:
    • Average age of population 63
    • General health of population
    • Used Premarin (CEEs) and Prempro (CEEs and MPA)


Factors that affect the outcome of hormone therapy

  • Form of estrogen used
  • Route of administration
  • Age at which hormones are taken
  • Health of individual taking hormones
  • Efficacy of cyclic vs. continuous therapy


Approaches to birth control

  • Combination pills
  • Progestin-only pills
  • Post-coital contraceptives


Combination pills

  • Progesterone decreases frequency of hypothalamic pulse generator
  • Estrogen inhibits LH/FSH at the pituitary
  • Monophasic, fixed-combination OCPs
    • Pills taken for first 21 days of cycle are identical
  • Multiphasic or varying-dose OCPs
    • Generally low dose of estrogen throughout cycle
    • Combined with various amounts of progestin
    • Dosages vary at very specific intervals during 21-day medication period


Progestin-only pills

  • Good for nursing mothers, patients with estrogen-contraindications
  • Less efficacious compared to combination pill
  • Decreases frequency of hypothalamic pulse generator
  • Take 3 weeks out of 4 week cycle
  • May be associated with irregular, low-grade, breakthrough endometrial bleeding


Post-coital contraceptives

  • Requires high doses of progestin
  • Interferes with implantation of ovum