Gonadal Steroids

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Types of Classes

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Estrogen, Progestins, SERM, Anti-Estrogen, Aromatase Inhibitors, GnRH Agonists, Anti-Progestins, Androgens, Anti-Androgens, Steroid Synthesis Inhibitors, 5a reudctase inhib.

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Estrogens rank
How they are made?

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17-B estradiol = most potent (E2)
OVARIES = main source pre-menopaus
E1 adipose stroma when estrione is synthesized from DHEA
Placenta use fetal DHEA -> E1 & E3

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Progesterone Feedback
How they are made?

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Dec. frequency of GnRH and LH pulse
Inc. Amplitude of LH & FSH
made and released from corpus luteum and placenta from hCG
LH + ovaries to make progesterone

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Estrogen Fxn

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Dec. FSH/LH amplitude during most of cycle
Inc. FSH/LH amplitude during mid-cycle

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Name 3 GnRH superagonists

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1. Leuprolide
2. Nafarelin
3. Goserelin

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Fxn of Aromotase

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Convert Testosterone --> Estrogen

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Progesterone Action

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Acts on thickened endometrium (uterus) to maintain it
Promotes transformation of endometrium into highly vascular "secretory endometrium" = good environment for fertilized ovum to implant

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Result of less frequent administration of GnRH analog:
Result of more frequent administration of GnRH analog:

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1. Ovulation (treatment of infertility)
2. Contraception (prevent pregnancy)

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Example of Progestins

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MPA - Medroxyprogesterone acetate
levanorgesterel (-gestrel)
norgestimate
norethindrone
ethynodiol diacetate

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Effects of Progestins

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contraceptive alone or w/ estrogen
(except MPA)
dec. GnRH pulse frequency
dec. aldosterone
inc. LDL, LPL, fat deposition

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Medroxyprogesterone

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used in HRT; it can oppose endometrial hyperplasia and cancer caused by estrogens; treat luteal phase support infertility; prevent premature labor

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Effects of Estrogen

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inc HDL; bone formation; coag factrs; salt and water retention; GH
dec. LDL; bone resorption; bowel motility

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Aromatase Inhibitors FXN

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prevent ovarian and peripheral synthesis of estrogens
rx: breast cancer but do NOT inc risk of uterine cancer/DVT

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Type 1 Aromatase Inhibitors
Ex and Fxn

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formestate
exemestane
Steroidal/substrate analogs, suicide inhibitors, irreversibly inactivate aromatase

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Type 2 Aromatase Inhibitors
Ex and Fxn

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anastrozole
letrozole
vorozole
non-steroidal; act reversibly at heme group of aromatase

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ANTI ESTROGEN

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fulvestrant
(17 alpha alkylamide derviative of estradiol)
Rx: tamoxifen-resistant breast cancer; no known estrogenic activity

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SERM- Selective estrogen receptor modulators
EXAMPLES

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tamoxifen
tomerifene
raloxifene
clomiphene

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Side effects of SERM

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2-3x increase DVTs and PE
2x increase endometrial cancer (except tomerifene!!!)
hot flashes; cataracts; nausea
dec LDL no change in HDL

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TAMOXIFEN

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Competitive estrogen receptor antagonist
Treatment of breast cancer, prosatic, STIMULATES prolif endometrium

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TOMERIFENE

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derivative of tamoxifen
txt breast cancer that is refractory to tamoxifen
DOES NOT inc risk of endometrial cancer

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RALOXIFENE

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dec proliferation/thickening of endometr.
prevents/treats post menopausal osteoporosis
dec risk of breast cancer
inc hot flashes

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Clomiphene
Fertility Drug

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blocks negative feedback of circulating estradiol on hypothal and pituitary
inc. output of GnRH, LH Aand FSH and stimulation of ovaries

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Anti-Progestins
EXAMPLES

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mifepristone
onapristone

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Anti-Progestins Fxn and Side effects

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antagonists for PR GR and AR
blocks the uterine PROGESTERONE receptor, causing the decidual breakdown and detachment of the blastocyst (used w/ misoprostol)

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Danazol

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Tx of endometriosis
Synthetic androgen used to inhibit output of FSH/LH in endometriosis
Removes hormonal stimulation

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FINASTERIDE

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5 alpha reducatse inhibitor BPH AND FDA approved for baldness;
inhibits only type II
SE = depression

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DUTASTERIDE

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5 alpha reducatse inhibitor BPH but not FDA approved for baldness;
inhibits both type 1 and 2

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ketoconazole

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anti-fungal; blocks testosterone synthesis increases estradiol: test ratio bc does NOT affect aromatase
gynecomastia, hepatoxicity and adresnal insufficiency

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spironolactone

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Aldosterone Antagonist (galactorrhea)
inhibits steroid binding; used in Polycystic ovarian syndrome to prevent hirsutism

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GnRH Analogs
fxn: suppress gonads

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goserelin
nafrelin, buserelin, triptorelin, leuprolide
initial flare but then dec FSH and LH

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GnRH Antagonists
Example and Fx

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Abarelix, Degaraleix, Cetreloeix, Ganirelix
Fxn: avoids initial flare treat prostate cancer

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Cytoproterone

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derivative of 17 alpha hydroxyprogesterone; acts as AR antagonist with weak PR and GR agonist activity; inhibits the action of androgens at the target organ
Rx: prostate Ca, BPH, hirustism

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Cytoproterone Acetate

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acetate --- suppresses LH secretion; reducing testosterone levels
Rx prostate ca, priapism, hirustism, OCP w/ estrogen; dec aldosterone bc inhibits 21 hydroxylase
SE: hepatoxicity, hyperK, osteoporosi

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FLUTAMINE

type of AR antagonist

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fx: prostate cancer, hirustism
ACTIVE METABOLITE = hydroxyflutamide
SE: hot flashes, mild hepatoxicity, gynecomastia, GI

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BICALUTAMINE

type of AR antagonist

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fx: prostate cancer, hirustism
less side effects

monotherapy with GnRH analog/castration

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NILUTAMINE

type of AR antagonist

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fx: prostate cancer only
combine with castration
worse side effect profile,
interstitial pneumonia