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Antithyroid Drugs
Thioureylenes = Methimazole/Propylthiouracil
o (-) tyrosyl iodination acting as substrate for
iodination by thyroid peroxidase
o Methimazole = most common, long half life pill
o Propylthiouracil
also (-) peripheral deiodination of T4 to T3
Tx acute thyroid storm
Main use long term stabilization
o Synthesis of hormone stops w/ in 12 hours but
symptoms take up to 4 months to stop
Slow turn over of pre-existing hormones
Large thyroid stores
Once stores are depleted, dose should be
decreased otherwise will result in
hypothyroid
Gonadal Given to pts w/ E2 def b/c of ovarian
Estrogens dysgenesis, dwarfism,
hypopituitarism/castration.
Chemical Structure/Function Begun at puberty age of 11ish
o Most potent naturally occurring estrogen is 17B- Post menopausal HRT
Estradiol o After menses stopped, there is a E2 for years
o Natural Estrogens are 18C w/ phenolic A ring/OH at o Indication for therapy = hot flashes, sweating, high
C3, and B-hydroxy or ketone at C17 risk of osteoporosis
o Phenol A ring needed for selective high affinity o risk of osteoporosis is most in smokers who are
binding to receptor thin, white, inactive, w/ a low Ca2+ intake and
o If given orally, its metab in liver and ineffective family Hx of osteoporosis
o Ethinyl estradiol are protected against liver metab o E2 admin in a cycle (3 weeks on, 1 week off) using
and can be given orally smallest dose
o Nonsteroidal = Diethylstilbestrol Given w/ progesterone
Synthesis o Prophylaxis of E2 in postmenopausal osteoporosis
o Androstenedione or T become estrogen using Best if Tx strated before bone loss occurs
Aromatase, a p450 dependent monooxygenease But not usually need b/c
CYP. Only 35% develop osteopor
This makes the A ring Exercise and Ca2+ diet also good
o Granulosa cells = main source of Estradiol (E2) in SE of E2
premenopausal women In women w/ oophorectomy/hysterectomy,
o In men and post menopausal its Fat this Tx is fine b/c no risk of endometrial
o During pregnancy its placenta cancer
MOA Adverse effects of E2
o Regulate transcription of genes o Post menopausal bleeding
o Enters cell by passive diff and binds nuclear Use smallest dose in cyclic fashion
estrogen receptor So if bleeding happens it will be during
o Once receptor is bound, it binds specific DNA withdrawal
sequences o Nausea/breast tender/hyperpigmentation/migraine,
Physiologic Effects cholestasia, hypertension
o At pubery GnRH released in pulsatile + o In post menopausal, risk of endometrial cancer
FSH/LH release w/ progestational agent, risk
o After 2 years, enough estrogen for endometrial o Endometrial cancer in pre-menopausal risk when
changes given estrogen + progestin
o estrogen can exert neg feedback on hypothalamus o Breast cancer w/ oral contraceptive
to GnRH release and thus FSH from pit. Contraindication
Effect on Pit LH is biphasic midcycle o Pts w/ estrogen dependent neoplasm like uterine
surge in LH ovulation cancer/breast cancer
o When ovaries are removed or are non-fxnal o unDx genital bleeding/liver disease/Hx of
Menstrual bleeding induced by admin and thromboembolism
subsequent stop of E2. o First Trimester Pregnancy
Can be induced by a single large dose or Drugs
by small doses for weeks o Natural
Dosage w/ in a defined range can result in Estradiol
menstrual flow even in absence of E2 Esradiol salts
withdrawal = Threshold dose Conjugated estrogens
When E2 is given w/o interruption and a o Synthetic
brief admin of progesterone Diethylstilbestrol
menstruation Ethinyl Estradiol
o Metabolic actions Alternative therapy
Cause salt and water retention edema. o Soy food
Water retention seen in latter half of cycle
Can LDL and HDL but also coag Progestins
factors that cause BP and sodium/water
retention Structure/Function
E2 thus causes an risk of CV disease o Needs ketone on A ring
Bioavailability o Substituents on C17 affect bio activity
o Absorbed via skin, mucous, GI tract Synthesis
o Oral limited b/c of liver metab o LH +Progesterone made in corpus luteum during
Therapeutic use 2nd half of cycle just before ovulation
o Oral Contraception o If ovum fertilized implantation trophoblast
o Postmenopausal Hormone Replacement Therapy makes hCG sustaining corpus luteum
(HRT) o 2nd/3rd month of preg, placenta makes estrogen and
o Primary hypogonadism progesterone
Physio Actions
o Prog release during cycle secretory endometrium Anti-estrogens
Abrupt decline in Prog means onset of
menses These include agents that
o Porg needed to maintain Preg, suppress menses and o Comp antag of E2 receptor
uterine contractility o (-) of E2 synth (eg, aromatase inhib)
o During preg, Prog + E2 prolif of mammary acini. o Agents that cause oppostive physio effects
o Prog secretion causes 1 degree C at midcycle (progestins and androgens)
before ovulation Comp antag of E2 receptor
MOA o Tamoxifen
o Nuclear receptor o Clomiphen
Absorption o Activated by hydroxyl at C4 of A ring
o Absorb in GI but metab by liver so not good orally Trans = antiestrogen
o Ethinyl moiety at C17 prevents degredation Cis = estrogen agonist
Therapeutic use o Effects
o Oral Contraception Ovary enlargement
o HRT see above Disrupts Neg feedback gonadotropin
o Endometriosis release gametogenesis steroidgen
To regress ectopic endometrial growth Clomphen Tx infertility
o Metastatic endometrial carcinoma Tamoxifen Tx E2 dep breast cancer
Palliative measure in recurring carcinoma risk of endometrial/uterine
Drugs cancer b/c its also a partial agonist
o Medroxyprogesterone Other antiestrogens
o Norethindrone o Leuprolide
o Norgestrel w/ cont use GnRH receptors
o Ethynodiol desensitized gonadotropin and steroid
release
Oral Contraceptives also used as anti-androgen
Aromatase inhibitor
Types o Anastrozole/Letrozole/Exemestane
o Combination = E2 + prog o Steroidal agent = Exemestane = suicide inhibitor of
o Biphasic and triphasic = E2 + Prog, where Prog aromatase
varies during cycle o Nonsteroidal = Letrozole/Anastrozole = interact
o Subcutaneous Progestin implant = Norgesterol reversibly w/ heme groups of CYPs (aromatase)
Long lasting o In post menopausal E2 conc is very high in the
o Single entity breast carcinoma b/c there are lots of aromatase in
Progetin alone = minipill those tumors.
Diethylstilbestrol = morning after pill Does not risk of endometrial/uterine
Nausea/vomit cancer
Norgestrel/ethinyl estradiol o In pre menopausal Letrozole used successfully
Norgestrel alone for induction of ovulation in an infertile woman
Single 600 mg mifepristone o Males have E2 levels like post penopausal women
MOA o Male breast cancer expresses E2/Prog receptor
o Inhbiti ovulation Tx w/ tamoxifen
o Suppress FSH and LH
o E2 (-) FSH release Antiprogestins
o Prog (-) E2 induced LH
Mifepristone
Adverse
o Der of Norethindrone
o CV
o Comp antag acts at Prog and glucocorticoid receptor
Thrombophlebitis/thromboembolism
o Action
Plateletl aggregation
Admin @ follic phase (-) ovulation by
Cerebral/coronary thrombosis
blocking Prog receptor at Pit/hypothal
Mild hypertension
mortality/morbidity Mid cycle surge of gonadotropins
o Cancer is suppressed and follicular
Vag/uterine/breast carcinoma development delayed
Hepatoma Admin at luteal phase block Prog action
Endometrial/cervical cancer in on uterus Prostaglandin release from
premenopausal on E2 only contraceptive endometrium and subsequent bleeding
Gluccocorticoid antag can be used to Tx
risk if comb w/ prog
Cushings
These induce metab of oral contracptives = effect
o Therapeutic use
o Rifampin/penicillin/tetracycline
Abortifacient in early preg when comb w/
o Anti HIV
Prostaglandin
o Entiepileptic
Single 600 mg dose use as post sex
o St. john wort
contraceptive
Use on progesterone sensitive tumors Adverse effects
Lipopristone used o Virilizing effects
In women masculinization
Androgens Acne, hair, voice, menses irregular
Long Tx can cause male pattern baldness,
T main hormone for men muscle, hypertrophy of clit
T made in ovary and adrenal cortex in women In children epiphyseal closure
T a prohormone for 2 classes Azoospermia due to inhiiton of
o 5a-reduced androgens = DHT gonadotropin secretion and conversion of
o Estrogens androgens to estrogens
Structure/function o Feminizing effect
o Oral ineffective b/c of liver metab Gynecomastia in men
o Esterification of 17B-hydroxy group = polarity = Aromatization to E2
solubility in parenteral admin Toxicity
o Alkylation of 17a inhibits hepatic metab and then o Edema w/ sodium retention
given orally o Jaundice
Synthesis Cholestatic hepatitis
o Conc of T high in males during o Long term Tx hepatic adenocarcinoma
Embryogenesisneonatal Drugs
Puberty o Testosterone
o LH/FSH regulate testicle growth/spermatogenesis o Testosterone salts
and steroidogenesis o Oxandrolone
o T can suppress LH and FSH release via feedback o Methyltestosterone
inhib of GnRH o Fluoxymesterone
DHT (aromatase) Estradiol used for o Danazol
neg feedback
Physio effects Anti-Androgens
o Anobolic effects
In hypogonadal/castrated men, admin of To manage hyperplasia and carcinoma of prostate
androgens urinary excretion of Tx virilization of females, precocious puberty
N/K/Na/Cl Leuprolide = GnRH analog/agonist
Nitrogen retention is seen to be used for o Cont Tx = LH and T secretion b/c desensitize
male muscle pattern GnRH receptors
o Anabolic and androgenic effects result from diff o Initially cause surge of T use finasteride so you
responses to the same hormone in diff tissues cut down the effect of T or use androgen receptor
o All anabolic steroids are androgenic antag
MOA o 1 week later, GnRH get desensitized stop making
o Androgen receptor gene regulation T
Therapeutic uses 2 other types
o Hypogonadism o Comp antags for androgen receptor
If testicle failure is complete, therapy w/ o Synthesis inhibitors
long acting T esters admin IM Finasteride
If begun at puberty, normal development o Inhibits 5a-reductase needed to make DHT
Will not respond to androgen therapy Cyproterone acetate
unless growth hormone also included o Comp antag of DHT for androgen receptor
o Catabolic state o Tx hirsutism
Improve nitrogen balance post Flutamide/Bicalutamide
surgery/injury o Non steroidal anti androgens
o Athletic performance o Comp antags
Promote muscle growth immature boys o Flutamide Tx of prostate cancer w/ leuprolide
and women of all ages o Bicalutamide = less hepatoxic than flutamide
But not really in mature men Abiraterone acetate
You would need massive doses to o Converted to abiraterone inhibits T synth by
have effect in mature men inhbiting CYP17A1 (17 alpha hydroxylase)
But androgen receptor in mature o Tx castration resistant prostate cancer
men are functionally saturated Spironolactone
o Stim of erythropoiesis o Comp antag
Effect on erythropoietin o Tx female hirsutism
Tx refractory anemia
Used in bone marrow fail, myelofib and
renal fail
o Carcinoma of breast
Palliatve Tx of breast cancer in
premenopausal women
Acting as an enti-estrogen
GnRH and GnRH antagonist
MOA
o GnRH analog (Leuprolide or Nafarelin) desensitize
GnRH receptors and cause the reduction of
estrogens
o GnRH antag (Cetrorelix) directly reduce estrogen
formation by blocking GnRH receptors
Endometriosis
o Caused by excess estrogen created each month
o Leuprolide (GnRH analog) use w/ low dose
hormone replacement therapy to diminish bone loss
o Nafarelin (GnRH) Nasal preparation
o Cetrorelix acetate (GnRH Antag)
Uterine fibroids
o May present w/ endometriosis
o Have estrogen receptors
o Leuprolide Used to decrease size before removal
by surgery
o Nafarelin same
o Cetrorelix acetate (GnRH Antag)
Oxytocin