Gonadal hormones Flashcards
what is the presentation of 17-alpha hydroxylase deficiency and tx for men and women?
- decreased sex hormones and cortisol, and increased in mineralocorticoids.
- pt presents c elevated BP and hypokalemia
- XY: decreased DHT may show cryptorchidism and indistinct genitalia.
- tx: androgens, glucocorticoids and anti-HTN
- XX: outwardly phenotypic female c normal internal sex organs but lack secondary sex characteristics
- -tx: estrogens, anti-HTN
what is the general mechanism of action of steroid hormones - estrogen, progesterone, testosterone?
- binds to the cytosolic receptor
- hormone-receptor complex (HRC) travels into nucleus
- activation of HRC leads to changes in the rates of transcription of steroid hormone regulated genes - modulate gene expression
what is the presentation of 21-alpha hydroxylase deficiency and tx?
- elevated sex hormones and decreased cortisol and mineralocorticoids.
- presents c decreased of BP, hyperkalemia, elevated renin activity and vol depletion
- over masculinization - pseudohermaphroditism in females
- tx: fluids + salt repletion; administer cortisol to decrease ACTH
what is the presentation of 11-beta hydroxylase deficiency and tx?
- elevated sex hormones and decreased cortisol, decreased mineralocorticoid (aldosterone) but increased increased 11-deoxycorticosterone.
- pt presents c elevated BP d/t elevated mineralcoticoid 11-deoxycorticosterone.
- over masculinization.
- tx: estrogens, anti-HTN
- what are sources of estrogen?
- what are the main estrogens?
- which one is more potent?
- ovary, adrenal gland, placenta, and in the blood from aromatization
- estradiol, estrone, and estriol
- estradiol
physiological effects of estrogens?
- sexual devel
- growth and devel of vagina, uterus, Fallopian tube and contribute to the breast enlargement.
- secondary sexual characteristics in females. - non-reproductive functions:
- reduce bone resorption; prevent the bone loss
- epiphyseal closure in long bones - pro-coagulation state
- increases factor II, VII, IX, X and XII
- decreases anti-thrombin III, protein C and S - favorable lipid profile
- increase HDL
- decrease LDL - effect on hormone levels
- increases the binding protein level of various hormones (cortisol, thyroxine, sex steroids)
- free hormone level is unaffected - increase cholesterol in bile- formation of gallstone
clinically used estrogens?
- estradiol (estrace)
- conjugated estrogen (premarin)
- ethinyl estradiol (estinyl)
- quinestrol (estrovis)
- estrone
- estradiol (estrace)
- conjugated estrogen (premarin)
- ethinyl estradiol (estinyl)
- quinestrol (estrovis)
- estrone
PK?
metabolize by CYP450.
combination c P-450 inducers can lead to failure of contraceptive effectiveness.
- estradiol (estrace)
- conjugated estrogen (premarin)
- ethinyl estradiol (estinyl)
- quinestrol (estrovis)
- estrone
Clinical uses?
- IM = long acting estrogen preparations are used in females c hypogandism.
- oral contraceptives in combo c progestins
- suppress FSH and LH secretion and inhibit ovulation. - postmenopausal hormone replacement therapy (HRT).
- HRT help and reduce hot flashes, prevent bone loss and fractures, decreased incidence of colon cancer, decreased urogenital atrophy, and increased feeling of well-being.
- estradiol (estrace)
- conjugated estrogen (premarin)
- ethinyl estradiol (estinyl)
- quinestrol (estrovis)
- estrone
Adverse effects?
- increased incidence of thromboembolism, changes in CHO & lipid metabolism, increased risk of elevated BP.
- increased incidence of breast & endometrial cancers
- migraine, cholestasis, and mood changes.
what is diethylstilbestrol (DES) and its a.e?
a nonsteroidal estrogen agonist
used in pregnancy result in female child to infertility and vaginal cancer.
- estradiol (estrace)
- conjugated estrogen (premarin)
- ethinyl estradiol (estinyl)
- quinestrol (estrovis)
- estrone
Contraindications?
- hx of thromboembolism
- breast & endometrial cancer
- pregnancy
- liver disease
Selective estrogen receptors modulators?
- tamoxifen
- raloxifene
- toremifene
tamoxifen
MOA?
antagonist effect on breast tissue but agonistic effect on liver, endometrium and bone.
tamoxifen
tx?
breast cancer
tamoxifen
A.E?
hot flushes (antagonist) and thrombosis (agonistic) risk of endometrial cancers.
toremifene
tx?
breast cancer and prevention of breast cancer in high-risk women
raloxifene
MOA?
antagonist at breast and but agonist at bone. no estrogenic effect on endometrium
no increased risk of endometrial cancer
raloxifene
Clinical applications?
- prophylaxis against breast cancers (in high risk pts)
2. prev of postmenopausal osteoporosis.
estrogen receptor antagonist?
fulvestrant
fulvestrant
Tx?
IM: breast cancer in tamoxifen resistant pts
fulvestrant
A.E?
hot flushes, infxn site rxns and HA.
Aromatase inhibitors?
- letrozole
- anastrozole
- exemestane
- letrozole
- anastrozole
- exemestane
MOA?
inhibit conversion of androgens to estrogen
- letrozole
- anastrozole
- exemestane
A.E?
hot flushes, decreased bone mineral density
- letrozole
- anastrozole
- exemestane
tx?
Oral: breast cancer as second line drugs following tamoxifen resistant
- letrozole
- anastrozole
- exemestane
which is irreversible?
exemestane
Clomiphene
MOA?
estrogen antagonist in hypothalamus and anterior pituitary -> prevents feedback inhibition of GnRH release by hypothalamus -> continued released of GnRH from hypothalamus -> LH and FSH from the pituitary -> ovulation
Clomiphene
Tx?
anovulatory infertility
Clomiphene
A.E?
- ovarian hyper-stimulation leading to enlargemnt of ovary
- multiple pregnancy
- hot flushes, nausea, vomiting, breast tenderness and weight gain
Progesterone
Physiological functions?
- induces secretary changes in the endometrium and is required for the maintenance of pregnancy
- decreased uterine contractility
- decreased gall bladder contraction
- high doses suppress the gonadotropin secretion leading to anovulation in women.
what are the progestins?
- Desogestrel
- norelgestromin
- etonogestrel
- norgestimate (newer prep c lesser androgenic effects)
- drospirenone (a spironolactone derivative)
- Desogestrel
- norelgestromin
- etonogestrel
- norgestimate
- drospirenone
Therapeutic uses?
- alone or c estradiol for contraception
- combo c estrogen = hormone replacement therapy
- decreased incidence of endometrial hyperplasia & carcinoma caused by unopposed action of estrogens - pt may have irregular bleeding
- used in ovarian suppression - tx of dysmenorrhea & endometriosis
- dx estrogen secretion & for responsiveness of endometrium. menstruation occurs after progesterone adm. in pt c amenorrhea - occurs after 5-7 days after.
- Desogestrel
- norelgestromin
- etonogestrel
- norgestimate
- drospirenone
Adverse effects?
long term:
- weight gain
- depression
- edema, acne
- decreased HDL, HTN
- thrombophlebitis
- cholestatic jaundice
antiprogestins?
- mifepristone
2. danazol
mifepristone
Pharmacodynamics?
competitive inhibitor of progesterone & glucocorticoid receptors
mifepristone
Uses?
- controversial “morning after” drug used as an abortifacient.
- given c PG-E or PG-F to increase myometrial contraction
mifepristone
A.E?
excessive bleeding, GI effects - nausea, vomiting, anorexia and abdominal pain.
danazol
pharmacodynamics?
- partial agonist of progestin, androgen and glucocorticoid receptors
danazol
PK?
inhibitor of P450 in gonadal steroid synthesis
danazol
clinical application?
endometriosis and fibrocystic disease of breast
danazol
A.E?
- hepatitis - abnl liver function tests and drug interaction d/t P450 inhibition
- masculizing effects - acne, hirsutism, mentrual disturbances.
what are some androgens?
DHT (most potent)
testosterone
androstenedione
testosterone
physiological effects?
- wolffian duct
- bone formation
- muscle growth
- spermatogenesis
Hihydroxytestosterone (DHT)
physiological effects?
- growth of external genetalia
- prostate growth
- scalp hair loss
- acne
- facial/body hair
what are some synthetic androgens?
- oxandrolone
- stanozolol
- fluoxymesterone
- oxymetholone
- nandrolone
- oxandrolone
- stanozolol
- fluoxymesterone
- oxymetholone
- nandrolone
clinical uses?
- substitution therapy in hypogonadism
- increase bone density (prev osteoporosis), could be used in increasing muscle mass (+ve nitrogen balance)
- some cases of aplastic anemia
- oxandrolone
- stanozolol
- fluoxymesterone
- oxymetholone
- nandrolone
A.E?
- over-masculinization
- in women could lead to hirsutism, suppression of menses, acne, and clitoral enlargement
- cholestatic jaundice (elevated serum transaminations)
- prostatic hypertrophy
- premature closure of epiphysis
what are some androgen receptor antagonists?
- flutamide - a substitued anilide
- bicalutamide
- nilutamide
Finasteride
MOA?
5-alpha reductase inhibitor
inhibit conversion of testosterone to DHT
finasteride
uses?
BPH and promotes hair growth
finasteride
A.E?
gynecomastia and impotence
Ketoconazole
MOA?
adrenal and gonadal steroid synthesis inhibitor
ketoconazole
uses?
prostate cancer but not first line drug
ketoconazole
A.E?
may have drug interactions c other steroids d/t inhibiting P450
what are some other antiandrogens?
- leuprolide
- goserelin
- nafarelin
- leuprolide
- goserelin
- nafarelin
MOA?
agonists at GnRH receptors: increase LH and FSH c intermitten adm.
Antagonists: decreased LH and FSH prolonged and continuous adm.
- d/t downregulate GnRH receptors in pituitary
- leuprolide
- goserelin
- nafarelin
uses?
- prostate cancer, uterine fibroids, and precocious puberty
- used in infertility c pulsatile dosing
spironolactone
MOA and uses?
decreased aldosterone and competes DHT.
used in Hirsutism
Cyproterone
MOA and uses?
- progesteronal effect suppresses LH and FSH
- used in hirsutism and to decrease excessive sexual drive in men.
degarelix and abarelix
MOA and uses?
- GnRH receptor antagonists, decrease LH and FSH
- used in prostate cancer
finasteride and dutasteride
MOA, uses, A.E?
- 5-alpha reductase inhibitors
- reducing the size of prostate gland.
- A.E = decreased libido and ejaculatory or erectile dysfunction
Terazosin, doxazosin, tamsulosin and alfuzosin
MOA, uses, A.E?
- alpha1-adrenergic antagonists
- relive outlet obstruction of the bladder by reducing the tension of prostatic smooth muscle in the prostate, prostate capsule, and bladder neck.
- A.E = orthostatic hypotension, dizziness.
what are the effects of the combination therapy of alpha1-adrenergic antagonist and 5 alpha-reductase inhibitors?
greatest reduction in the sxs of BPH, such as acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infxns.
