B-22. Estrogen And Antiestrogen. Flashcards
The function and products of the ovaries
The ovary -Gametogenic and endocrine functions o Dormant before puberty o At puberty, the ovaries begin a 30-40 year period of cyclic function (menstrual cycle) o Menopause -Function controlled by GnRH ( hypothalamus) – FSH, LH (pituitary) - Ovarian hormones: oEstrogens, progestins, others
Review menstrual cycle
Review menstrual cycle
Natural Estrogen (key drug to learn plus others)
Estradiol (major secretory product of the ovary and major drug to learn)
Estrone and estriol (formed in the liver from estradiol or in the peripheral tissues from androgens i.e. androstenedione)
Equine estrogen
Phytoestrogen
Synthetic estrogen with steroidal structure
Ethinylestradiol
Mestranol, quinestrol
Non-steroidal synthetic estrogen
Dienestrol, diethylstilbestrol, chlorotrianisene, methallenestril, benzostrol, hexestrol, methestrol
Pharmacokinetics of natural estrogen
Natural estrogens:
o High first pass metabolism
▪ High ratio of hepatic to peripheral effects
• Increases the incidence of some side effects:
o Undesired: coagulation, biliary
o Advantageous: lipid profile
• To avoid this: transdermal administration, by injection, or local application (vaginal use)
▪ Conjugated estrogens (e.g. estradiol valerate) – i.m. depot
o Estradiol binds to SHBG (and to albumin) in the circulation
o Excreted partly in bile – enterohepatic cycling
Synthetic estrogen pharmacokinetics and MOA of estrogen
Good oral bioavailability
IC receptor leading to gene activation
Pharmacological effects of estrogen
Pharmacological effects of estrogens
- Estrogens promote proliferation of endometrium and breast tissue
- Cooperation with progestins
- Female sexual maturation and growth, secondary sex characteristics, female
libido
- Endometrial effects – development of endometrial lining
- Metabolic and cardiovascular effects
o Normal structure and function of skin and blood vessels
o Decrease the rate of bone resorption
o Higher levels of CBG, TBG, SHBG, transferrin, fibrinogen
o Mild, advantageous changes in lipoprotein, triglyceride and cholesterol
levels
- Blood coagulation is enhanced (increased synthesis of coagulation factors)
- Activation of the stress and the sympathetic systems
- Sodium retention, edema
Clinical use of estrogen
Clinical uses of estrogens
- Hormone replacement
o Primary hypogonadism
▪ Replacement therapy, starting at age 11-13
o Postmenopausal hormone therapy
▪ Either estrogen monotherapy or in combination with progestins
(if the patient has an intact uterus)
- Estrogens + progestins
o Hormonal contraception
o Suppression of the ovarian functions
▪ Intractable dysmenorrhea, polymenorrhea, dysfunctional
bleeding, premenstrual syndrome
▪ Treatment of hirsutism and amenorrhea due to excessive
secretion of androgens by the ovary
Adverse effects of estrogen
Adverse effects of estrogens
- Increased risk of endometrial carcinoma
o Progestins are protective
- Increased risk of breast cancer
o Progestins are not protective
- Increased blood coagulation
o Increased risk of stroke and venous thrombosis
- Postmenopausal uterine bleeding
- Nausea, breast tenderness, hyperpigmentation
- Increase in frequency of migraine headaches, cholestasis, gallbladder disease
- Diethylstilbestrol:
o Increases the risk of vaginal adenocarcinoma in women whose mothers were treated during pregnancy – should be avoided during pregnancy
Contraindications of estrogen
Contraindications of estrogens
- Patients with estrogen-dependent neoplasms (endometrial, breast cancer)
- Patients with undiagnosed genital bleeding
- Liver disease
- History of thromboembolic disorder
- Heavy smokers
SERM drugs
Estradiol Clomifen Tamoxifen Toremifen Raloxifen
SERM with greatest effects in endometrium, breast, bones, vasomotor effects, and is advantageous on lipid levels
Estradiol
SERM with no effects in endometrium, breast, bones, vasomotor effects, and is advantageous on lipid levels
Clomifen
Tamoxifen has no effect where?
Breast
