Estrogens and Progestins Flashcards
Where are estrogens synthesized?
Ovary, liver (from estriol), and peripheral tissue (from androgens)
Where are progestins synthesized?
Ovary, testis, adrenal from circulating cholesterol
Placenta during pregnancy
Where are androgens synthesized?
Testis (95%) Adrenal glands (5%)
What is the more estrogenic/active estrogen?
Estradiol 17B (E2)
What are the natural estrogens?
Estradiol 17B (E2)
Estrone (E1)
Estriol (E3)
What are the synthetic steroidal estrogens?
Ethinyl estradiol
Mestranol
Quinestrol
What are the synthetic non-steroidal estrogens?
Diethylstilbestrol (DES)
Chlorotrianisene
Methallenestril
Which cells synthesize and secrete LH and FSH?
Gonadotrophs
Action of LH and FSH in females
LH stimulates theca cells to synthesize androgen which is aromatized to estrone (E1) and estradiol (E2) in granulosa cells via FSH action
Action of LH and FSH in males
LH stimulates testicular Leydig cells to increase the synthesis of testosterone, which diffuses to neighboring sertoli cells
Which cells synthesize and secrete Inhibin A, Inhibin B, and Activin
Sertoli cells
Granulosa cells
What is the action of inhibin on the gonadotrophs?
inhibits the release of FSH
what is the action of activin on gonadotrophs?
stimulates FSH release
What is the enzyme that converts testosterone to estrogen?
aromatase
Reproductive actions of estrogen
Growth, development, structural maintenance of primary and secondary female sex characteristics Changes at puberty Regulation of menstrual cycle Growth of uterine endometrium Secretion of thin cervical mucus
Metabolic actions of estrogen
Increase HDL, decrease LDL Increase cholesterol saturation of bile Increase BP via renin Promote thrombosis (clotting factors) Decrease bone reabsorption Increase liver protein synthesis
CNS actions of estrogen
Positive effects on mood
Positive effects on cognition and memory
Major clinical uses of estrogens
Oral contraceptives
HRT during menopause
HRT for delayed puberty or hypogonadism in women
Rx of perimenopause, dysmenorrhea, oligomenorrhea, delayed puberty
Rx of acne
Estrogen preparations
Conjugated estrogens Estradiol Estradiol transdermal Ethinyl estradiol (syn steroid) Diethylstilnestrol (DES) (syn non-steroid)
Estrogen indictions
Vasomotor symptoms of menopause (flushing)
Vulvar and vaginal atrophy
Female hypoestrogenism secondary to hypogonadism castration or primary ovarian failure
Retard bone loss/ osteoporosis
Estrogen side effects
Nausea and vomiting Edema Headache Breast tenderness Venous thrombosis Breakthrough bleeding Estrogen alone (w/o progesterone) causes endometrial hyperplasia and possible endometrial carcinoma Increase adenocarcinoma of vagina (DES)
Estrogen contraindications
Breast and endometrial cancers Cerebral vascular coronary artery disease Benign or malignant liver tumors Severe hypertension Pregnancy Female smokers over 35 Thrombotic disorders
Selective Estrogen Receptor Modulators (SERMs)
Tamoxifen
Clomiphene
Raloxifene
Tamoxifen (SERMS) Indication
Prevention, palliative, adjuvant therapy for breast cancer (ER+)
pre or post menopausal
Tamoxifen (SERMS) MOA
Estrogen receptor antagonist in the breast tissue, partial agonist in the endometrium and bone
Tamoxifen (SERMS) side effects
Malignant neoplasm of endometrium Cataract Pulmonary embolism Hot flashes Abnormal menstruation Vaginal discharge
Tamoxifen (SERMS) contraindication
Deep vein thrombosis or pulmonary embolism
Pregnancy
Tamoxifen and endometrial cancer
Tamoxifen is associated with 4-6 fold increase in incidence of endometrial cancer
Administered for no more than 5 years to minimize risk
Clomiphene (SERMS) indication
Female infertility due to ovulatory disorder
Clomiphene (SERMS) MOA
Estrogen receptor antagonist in hypothalamus and pituitary gland, partial agonist in ovaries
Clomiphene (SERMS) Side effect
Thromboembolism
Ovarian cysts and hypertrophy
Flushing and vasomotor symptoms
Abdominal discomfort
Clomiphene (SERMS) contraindications
Pregnancy Thyroid or adrenal dysfunction Liver disease Endometrial carcinoma Ovarian cysts Intracranial lesion
Benefit of Clomiphene over exogenous FSH
Clomiphene is rarely associated with the ovarian hyperstimulation syndrome
Raloxifene (SERMS) Indication
Osteoporosis prevention and treatment
Raloxifene (SERMS) MOA
Estrogen receptor agonist in the bone and estrogen receptor antagonist in uterus and breast
Raloxifene (SERMS) Side Effects
Retinal vascular occlusion
Venous thromboembolism
Hot flashes
Leg cramps
Raloxifene (SERMS) Contraindication
Pregnancy
History or presence of venous thromboembolism
What is the effect of Raloxifene on invasive breast cancer?
Decreases the risk of invasive breast cancer is POSTmenopausal women with osteoporosis
Estrogen receptor antagonists
Fulvestrant
Fulvestrant indications
Rx of estrogen receptor+ metastatic breast cancer in POST menopausal women with disease progression following anti-estrogen therapy (ex. Tamoxifen)
Fulvestrant MOA
Competitively inhibits estrogen binding to receptor
Estrogen receptor antagonist
Fulvestrant Side Effects
Nausea Asthenia (lack of strength) Pain Vasodilation (hot flashes) Headache
Fulvestrant contraindication
Pregnancy
Does fulvestrant have any agonist activity?
NO
What is the action of aromatase?
converts testosterone to estrogen
Aromatase Inhibitors
Anastrozole
Letrozole
Exemestane
Formestane
Aromatase Inhibitors Indications
Treatment and prevention of estrogen receptor positive breast cancer (early, locally advanced, or metastatic)
Anastrozole and Letrozole MOA
Competitive inhibitors of aromatase (reversible)
Exemestane and Formestane MOA
Irreversible inhibitors of aromatase
Aromatase Inhibitor side effects
OSTEOPOROTIC FRACTURES Thromboplebitis Hypercholesterolemia Profuse vaginal bleeding Peripheral edema Rash Nausea Arthralgia Bone pain Headache Depression Dyspnea
Aromatase inhibitors vs. SERMs for the treatment of breast cancer
Aromatase inhibitors may be more effective than SERMs
Physiological actions of progesterone
Regulation of menstrual cycle Induces secretory uterine endometrium (implantation) Thick, viscous cervical mucus Increases body temperature Maintain pregnancy Development of mammary gland
Clinical uses of progestins
Oral contraceptives
HRT in menopause
Dysmenorrhea, oligomenorrhea, endometriosis, PCOS
What are the three major types of oral contraceptives?
Progestin only
Combination (estrogen + progesteron)
Emergency
Progestin only contraceptives
Norgestrel
Norethindrone
Medroxyprogesterone acetate
Etonogestrel
Progestin only contraceptives indication
Contraception
Progestin only contraceptives MOA
Alter frequency of GnRH pulsing and and decrease anterior pituitary gland responsiveness to GnRH
Alter tubal peristalsis, endometrial receptivity, cervical mucus secretions
Progestin only contraceptives Side Effects
Irregular periods Breast tenderness Nausea Dizziness Headaches
Progestin only contraceptives Contraindications
Acute liver disease
Benign or malignant liver tumors
Known or suspected breast cancer
Pregnancy
Route of administration of progestin only contraceptives
Medroxyprogesterone: given parenterally every 3 months
Etonogestrel (implant): effective for 3 years
Levonogestrel (oral): emergency contraception
Estrogen-Progestin Combinations
Estrogens: Ethinyl estradiol, mestranol
Progestins: Norgestrel, Levonorhestrel, Norethindrone, Norethindrone acetate, Ethynodiol, Norgestimate, Gestodene, Desogestrel, Drospirenone
Combo OC:
EE+ norgestrel
EE+ drospirenone
Estrogen-Progestin Combinations Indications
Contraception
Estrogen-Progestin Combinations MOA
Suppress GnRH, LH and FSH secretion and follicular development, inhibit ovulation
Alter tubal peristalsis, endometrial receptivity and cervical mucus secretions
Estrogen-Progestin Combinations Side Effects
Arterial and venous thromboembolism Pulmonary embolism Cerebral thrombosis Gallbladder disease Hypertension Hepatic neoplasm Abnormal menstruation Breakthrough bleeding Breast tenderness Bloating Migraine Weight change
Estrogen-Progestin Combinations Contraindications
Breast cancer Endometrial cancer Estrogen dependent neoplasms Cerebral vascular or CAD Cholestatic jaundice Liver tumors Severe hypertension Prolonged immobilization Pregnancy Female smokers >35 Thrombotic disorders
Which progestins have the highest androgenic activity?
Norgestrel and levonorgestrel
Progesterone Receptor Antagonist
Mifepristone (RU-486)
Mifepristone (Progesterone Receptor Antagonist) Indication
Abortion (through day 49)
Mifepristone (Progesterone Receptor Antagonist) MOA
Inhibits progesterone binding to receptor
Mifepristone (Progesterone Receptor Antagonist) Side Effects
Prolonged bleeding Bacterial infections Sepsis N/V/D Cramps Headache
Mifepristone (Progesterone Receptor Antagonist) Contraindications
Chronic adrenal failure Ectopic pregnancy Hemorrhagic disorders Anticoagulation therapy IUD
Emergency (morning after) contraception indication
Medication to prevent unwanted pregnancy after unprotected intercourse
Emergency (morning after) contraception
Two doses of “minipill”
0.75 mg of levonorgestrel (12 hrs)
Emergency (morning after) contraception MOA
Potent progestin, blocks the LH surge, disrupting normal ovulation, produces endometrial changes for implantation
Emergency (morning after) contraception timing
Take first dose within 72 hours of intercourse, 2nd dose 12 hours after 1st dose
Emergency (morning after) contraception side effects
N/V
Headache
Dizziness
Mastalgia
Indications for HRT
Vasomotor instability
Mood changes
Urogenital atrophy
Osteoporosis
HRT preparations
Conjugated equine estrogens Micronized estradiol Conjugated synthetic estrogens Transdermal estrogens Vaginal ring Medroxyprogesterone Micronized progesterone Combination products (E+P)
Effects of HRT
Relief from vasomotor symptoms, urogenital atrophy, recurrent urinary symptoms
Relief from fatigue, depression
Maintenance of bone density
HRT Side Effects
E: nausea, mastalgia (breast pain), headache, fluid retention
P: weight gain, headache
Estrogen alone associated with ____ risk of endometrial carcinoma
5-8 x increase
