Pharmacology of Estrogens and Progestins

Question 1

Principal estrogens in humans

Answer 1

• 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

Question 2

Estrogen-like compounds in humans

Answer 2

• 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

Question 3

Cell types in which estrogens are made

Answer 3

• 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

Question 4

Site of progesterone biosynthesis

Answer 4

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

Question 5

Steps of estradiol synthesis

Answer 5

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

Question 6

Negative feedback in estrogen biosynthesis

Answer 6

• 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

Question 7

MOA of estrogens

Answer 7

• 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

Question 8

MOA of progestins

Answer 8

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

Question 9

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

Answer 9

• 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

Question 10

Other clinical indications for estrogen/progestin agonists & antagonists

Answer 10

• 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

Question 11

Estrogen preparations

Answer 11

• 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

Question 12

Progestin preparations

Answer 12

• 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

Question 13

Estrogen/progestins pharmacology

Answer 13

• 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

Question 14

Aromatase inhibitors

Answer 14

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

Question 15

Clinical uses of aromatase inhibitors

Answer 15

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

Question 16

Risks of administering estrogens/progesterones

Answer 16

• 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

Question 17

Benefits of administering estrogens/progesterones

Answer 17

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

Question 18

Selective estrogen receptor modulators (SERMs)

Answer 18

• 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

Question 19

SERMs approved for use in the US

Answer 19

• 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

Question 20

Women’s Health Initiative

Answer 20

• 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)

Question 21

Factors that affect the outcome of hormone therapy

Answer 21

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

Question 22

Approaches to birth control

Answer 22

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

Question 23

Combination pills

Answer 23

• 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

Question 24

Progestin-only pills

Answer 24

• 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

Question 25

Post-coital contraceptives

Answer 25

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