Gonadal Hormones Flashcards
Name 3 natural estrogens?
- Estrone (E1)
- Estradiol (E2)
- Estriol (E3)
Where do conjugated estrogens come from?
• Conjugated estrogens are blended equine estrogens
either isolated from the urine of pregnant mares or
synthetically produced.
Name 2 synthetic estrogens?
Steroidal
• Ethinyl estradiol
• Mestranol (pro-drug converted to ethinyl estradiol)
MOA of estrogens?
Mechanism of action
• Estradiol bind to the estrogen receptor to form a
steroid hormone receptor complex
• Hormone-receptor complex → cell nucleus
→ changes in gene expression
Effects of Estrogen: Female maturation, endometrial, and Metabolic?
Female Maturation
• Development of female secondary sex characteristics
Endometrial
• Endometrial proliferation
Metabolic
• The effects of estrogens on selected aspects of mineral,
lipid, carbohydrate, and protein metabolism are
important for understanding their pharmacological
actions.
Effects of Estrogens: Bone, Lipids, and Coagulation?
Bone
• Decreases resorption of bone (increases mass)
Lipids
• Increase in HDL and decrease in LDL
Coagulation
• Increase hepatic production of factors 2, 7, 9 & 10 and fibrinogen
• Decreases antithrombin III activity
• Increases risk of thromboembolic events
Effects of Estrogen: protein synthesis, vasculature, and fluid balance? Other effects?
Protein Synthesis
• Increase in hepatic production of binding proteins eg, SHBG
Vasculature
• Increase production of NO
• Increase production of prostacyclin
Fluid Balance
• Na+ and H20 retention
Other Effects
• Reproductive Function
• Sexual Behavior
• GI Tract
PK of Estrogens?
Route of Delivery
• Oral, parenteral, intravaginally, or transdermal patch
Metabolism
• Conjugation by cytochrome enzymes
• Use enterohepatic circulation (metabolized in liver, excreted in bile, hydrolyzed by intestinal bacteria and reabsorbed as active drug)
Clinical uses of estrogens?
Postmenopausal Hormonal Therapy
• Decreases risk of osteoporosis (does not treat
osteoporosis)
• Reestablishes feedback on hypothalamic control of NE
secretion, leading to decreased frequency of hot flashes
• Reverses postmenopausal atrophy of the vulva, vagina,
urethra, and trigone of the bladder
Primary Hypogonadism
• Treatment begun with estrogen between ages 11-13
• Progestin added after first uterine bleeding
Treatment of Androgen-Dependent Prostate cancer
Oral Contraceptives
Menstrual Abnormalities
Minor AE of estrogens and Contraindications?
Minor • Uterine bleeding • Nausea • Breast tenderness • Melasma • Peripheral edema
Contraindications
• Cytochrome inducers can lead to reduction in efficacy
Moderate to severe AE of Estrogens?
Moderate/Severe • Increased risk of endometrial cancer (can be offset by combining estrogen with progestin) • Increase in frequency of migraines • Cholestasis and gallbladder disease • Hypertension • Thromboembolism • Depression
Names 3 Selective Estrogen Receptor Modulators(SERMS)
Tamoxifen
Raloxifene
Clomiphene
MOA of each SERM?
Mechanism of Action
They bind to estrogen receptors but can act as
antagonists or agonists depending on the tissue.
Tamoxifen – Antagonist in breast tissue; agonist in nonbreast tissues (endometrium, liver, bone)
Raloxifene – Antagonist in uterus and breast tissue;
agonist in the bone (inhibits resorption)
Clomiphene – Antagonist in hypothalamus (prevents
normal feedback inhibition)
Clinical Use of each SERM?
Tamoxifen
• Prevention and treatment of hormone-responsive breast cancer
Raloxifene
• Prevention of hormone-responsive breast cancer
• Prevention and treatment of osteoporosis in postmenopausal
women
Clomiphene
• Treatment of infertility associated with anovulatory
cycles (eg, PCOS)
AE of Tamoxifen?
Tamoxifen
• Hot flashes and nausea
• Endometrial hyperplasia (increased risk of cancer)
• Thromboembolism
AE of Raloxifene?
Raloxifene • Hot flashes and nausea • Leg cramps • Thromboembolism • NO RISK of endometrial hyperplasia
AE of Clomiphene?
Clomiphene
• Hot flashes, nausea, vomiting, weight gain, breast
tenderness
• Ovarian hyper-stimulation
• Multiple simultaneous pregnancies (10%)
• Visual disturbances
Name on Selective estrogen receptor degrader/downregulator?
Fulvestrant
MOA and clinical use of SERDs?
Mechanism of Action
They bind to estrogen receptors and cause the receptor to be degraded and thus downregulated in all tissues
Clinical Uses
Adjuvant treatment of hormone-receptor positive
metastatic breast cancer that is resistant to first-line
antiestrogen (tamoxifen) therapy
PK and AE of SERDS?
Pharmacokinetics
Given IM
Adverse Effects
• Hot flashes
• Arthralgias
• Myalgias.
Name 3 aromatase inhibitors? MOA of each?
Anastrozole (non-steroidal)
Letrozole (non-steroidal)
Exemestrane (steroidal)
Mechanism of Action
Inhibit peripheral conversion of androgens to estrogen
• Anastrozole and Letrozole are competitive, reversible
inhibitors
• Exemestrane is an irreversible inhibitor
Clinical use and AE of aromatase inhibitors?
Used as adjuvant chemotherapy in estrogen receptor positive breast cancer
AE • Hot flashes • Nausea • Fatigue • Alopecia • Dermatitis
Name Natural and Synthetic progestins(there are 6 synthetic)
Natural Progestins
• Progesterone
Synthetic Progestins • Medroxyprogesterone • Norgestrol • Norethindrone • Norgestimate • Desogestreol • Drospirenone
MOA of Progestins?
Mechanism of action
• Progestins enter the cell and bind progesterone
receptors
• The lipid-receptor complex binds to a progesterone
response element (PRE) and activates gene expression
