Exam 2: Lecture X, Estrogens Flashcards
Primary Sex hormones Females
Estrogen and progesterone
Production of Estrogen and Progesterone is regulated by…
FSH and LH
FSH effects
estrogen secretion
Estrogen secretion from ovaries
LH effects
progesterone secretion
Progesterone secretion from ovaries
Most potent ovaries estrogen in women is….
estradiol (estrogen)
Highly bound to sex hormone-binding globulin (SHBG)
effective orally, due to intensive hepatic metabolism semisynthetic agents are used
Estrogen receptors found mostly in…
cells of principal targets
also found in AP/Hypothalamus
Principal targets are…
reproductive system
ie. Uterus, vagina, and mammary glands
Progesterone effects on estrogen receptor expression
decreases
Prolactin effects on estrogen receptor expression
increases in mammary gland, liver but no effect uterus
Estrogen Effects 1
growth of genital structure breast development development of secondary sexual characteristics maturation of OVA sexual behavior modifications
Estrogen effects 2
Metabolic effects changes in serum protein level preservation of bone mass increase absorption in GI tract increase plasma triglyceride level enhanced blood coagulability
Estrogen clinical use
stimulate development of secondary sex characteristics (11-13yr old)
replacement therapy in hypo-ovarian condition menopausal symptom treatment postmenopausal replacement therapy vaginitis itching pain during sex genital swelling pain peeing contraception prostate cancer
Estrogen pharmacokinetics
natural and synthetic used clinically
absorbed well GI
can be absorbed skin - mucous membranes, given as patches or creams
Natural estrogens metabolism in liver speed
fast
Synthetic estrogens metabolism in liver speed
slow
Long term doses in women associated with following toxicity…..
2-3 fold increase gall-bladder disease
3 fold increase venous thrombosis
1.5 fold increase stroke
hypertension
Moderate doses in women associated with following toxicity…..
stimulatory effects vagina,uterus, breast tissue
breast tenderness
endometrial hyperplasia
breakthrough bleeding
hyperpigmentation
Estrogens contraindications
estrogen dependent tumors
vaginal bleedings
liver disease
gall-bladder disease
history of thromboembolism
cig smoke significantly increase risk of serious cardia event
Estrogen antagonist
have small effect by themselves, but they compete with natural estrogens for binding sites
Tamoxifen/Clomiphene
Tamoxifen (nolvadex)
Treatment of estrogen-dependent breast cancer, blocks estrogen receptors in tumor. binds to receptor in nucleus
targets breast/uterus and bones
v important non-steroidal agent
Little toxicity, prevent osteoporosis
Clomiphene (Clomid)
Infertility treatment
non-steroidal agent
targets Hypo/AP, inhibits estrogen receptors
prevents normal regulation by neg feedback
increases secretion of GnRH, LH + FSH…induce ovulation
Clomiphene (Clomid) Adverse effects
Adverse effects are mild and disappear with drug discontinuation
headaches
skin allergies
reversible hair loss
eye symptoms
Contraindication:
-patients with enlarged ovaries (reported risk of ovarian cancer)
Progesterone is synthesize and secreted from…
placenta, Adrenal cortex and testes
Progesterone metabolized in…
liver and has a very short half life and bioavailability
Progesterone major effects
through negative feedback affects hypothalamus and pituitary, decrease release of LH
raises body temp
development of secretory tissue in boobies
vascularization of uterine wall
maturation of uterine endometrium
If implantation of ovum has not occurred, progesterone secretion….
stops
If implantation of ovum has occurred, progesterone secretion….
continues
Progesterone Toxicity
is low
increase BP, decrease HDL
major clinical use of progestins….
oral or implanted contraceptives
progesterone agonists
Progesterone agonist indication
Uterine bleeding dysmenorrhea premenstrual syndrome Endometriosis suppression of postpartum lactation carcinoma hypoventilation
Mifepristone (RU 485)(Mifeprex)
An orally active steroid antagonist of progesterone and glucocorticoids
Binds to cytosolic steroid receptors of these hormones and alters genes
Abortifacient (Europe) – single dose followed by PGE1(misoprostol) administration
Abortion with low incidence of serious toxicity
Possibility of vaginal bleeding requires administration by a physician
Reportedly used in malignancy treatment, treat endometriosis
Progesterone Antagonists
Mifepristone (RU 485)(Mifeprex) Adverse effects
Nausea Vomiting Abdominal pain Pelvic pain Vaginal bleeding
Danazol (Danocrine)
An orally active steroid antagonist of:
- progesterone, glucocorticoids and androgen receptors
Binds with steroid transport protein in the blood
Inhibits several P450 enzymes in gonadal steroid synthesis
Treatment of endometriosis and fibrocystic disease of the breast
Danazol (Danocrine) side effects
Weight gain Edema Decreased breast size Acne Oily skin Libido changes Muscle cramps
2 major types of oral contraceptives
Combination estrogen-progestin tablets and Progestin only pills
- Typically, progestins are more potent, and have more lasting physiological effect
Monophasic combination prep
constant dosage during the cycle
taken from 21 consecutive days out of 28
Biphasic and triphasic combination prep
dosage of 1 or both components is changed
once or twice during the cycle
Combination Estrogen-Progestin Tab MOA
Estrogen inhibit FSH = follicle development
Progestin inhibit LH = ovulation
affects uterine tubes/endometrium
makes cervical mucus inhospitable for sperm
Results in endometrium unsuitable for implantation
Progesterone only pill…
taken continuously
contraceptive less reliable
doesn’t interfere with lactation
some effects of chronic use hormonal contraceptives
Depression of ovarian function Follicular development is minimal, and corpora lutea is absent Ovaries become smaller Cervix shows some hypertrophy and polyp formation Some breast enlargement Tendency to suppress lactation Some detrimental effect upon the liver Weight gain Nausea Mood changes Skin pigmentation Reversible hypertension
Severe disorders related to hormonal contraceptives
** Incidences of serious toxicity is low **
Serious changes in blood coagulation
Thromboembolism
Venous thromboembolic disease
Myocardial infarction (related to smoking)
Stroke
Carcinogenesis – a complicated picture:
reduced incidences of endometrial and ovarian carcinoma and
- reduced incidences of endometrial hyperplasia
- cervical carcinoma – unchanged
- breast cancer – no definite conclusion
Benefits of oral contraceptives
Relatively safe method of contraception for young women, not so much for older
reduction in dose reduces mild/severe adverse effects in young women
Infertility treatment
Targets hypothalamus and anterior pituitary gland
Inhibits estrogen receptors in the hypothalamus and anterior pituitary gland
Prevents normal regulation by the negative feedback
Increases secretion of GnRH, also LH + FSH - surge gonadotropin secretion
Surge of gonadotropin secretion – induces ovulation
Clomiphene Pharmacokinetics
Nonsteroidal partial antagonist induces ovulation
well absorbed orally
excreted primarily in urine
significant protein binding, enterohepatic circulation
Clomiphene Adverse effects
Adverse effects are mild and disappear with the drug discontinuation:
- headaches
- skin allergies
- reversible hair loss
- eye symptoms
Contraindication:
- patients with enlarged ovaries (reported risk of ovarian cancer)
Menotropin (Repronex)
Combination of LH+FSH in different proportionally (originally 1:1)
- originally extracted from urine of postmenopausal women (hMG)
- recombinant gonadotropins to a great degree replaced human gonadotropins
- daily injections (IM, SC) for 10 days
used in men to stimulate sperm production
Recombinant human (FSH) followed by one-two large doses of LH
