Intro to sex hormone pharmacology

What is the beginning of the sex hormone axis?

hypothalamus

What hormone does the hypothalamus produce and where does it act?

GnRH

anterior pituitary

What hormones does the anterior pituitary produce and where do they act?

LH and FSH

gonads

What effect does FSH have on the gonads?

produces estrogen

What effects does FSH have on the gonads?

Produces androgens and progesterone

Why is feedback of sex hormones different in female?

women have high estrogen during days 12-14
leads to positive feedback with hypothalamus and anterior pituitary

What is the normal effect of androgens and estrogens on the hypothalamus and anterior pituitary females and males?

negative feedback
decreases GnRH --> decrease in sex hormones

What steroids have the highest potency?

DHT (dihydrotestosterone) - androgen receptor (AR)
E2 - estradiol, estrogen receptor (ER)
P4 - progesterone, progesterone receptor (PR)

How do steroids travel around the body?

bound to protein --> to be activated must be released

Where do GnRH agonists/antagonists act upon the sex hormone axis?

Hypothalamus

Where do gonadotropins act on the sex hormone axis?

On LH and FSH - act on released hormones by anterior pituitary

Where do Steroid receptor antagonists/agonists, selective receptor modulators, and enzyme inhibitors act in the sex hormone pathway?

on hormones released from gonads
androgens, progesterones, and estrogens

What is the common ending for GnRH agonists?

-relin
except leuprolide

Name some GnRH agonists

Leuprolide - exception
Histrelin
Goserelin
Triptorelin
Nafarelin

What action does GnRH agonists have on the GnRH receptor?

Activate it

What are example indications for GnRH agonists?

Endometriosis
Uterine fibroids
Prostate cancer
Breast cancer
Precocious puberty

What is the common ending to injected GnRH antagonists?

-relix

What is the common ending to oral GnRH antagonists?

-golix

Name some GnRH antagonists

Cetrorelix
Ganirelix
Degarelix
Rellugolix
Elagolix

Name oral GnRH antagonists

Relugolix
Elagolix

Name some injectable GnRH antagonists?

Cetrorelix
Ganirelix
Degarelix

What are indications or GnRH antagonists?

Fertility therapy - stop early ovulation
Prostate cancer
Endometriosis - regulates hormones

What are the delivery forms of GnRH agonists?

SC injections
IM injection "depot"
Subcutaneous implant
Intranasal spray

What happens with a single use of GnRH agonists?

Stimulates LH and FSH release

What happens with continuous GnRH agonists?

continuous activation leads to desensitization
shuts off LH and FSH release - thru - feedback

A decrease in LH and FSH leads to?

decreased in stimulation of gonads
decreased sex hormone

What are problems with GnRH agonists?

can increase sex hormones temporarily worsening of symptoms (tumor flare when used for cancer)
Inhibition is ALL or NOTHING
long-term suppression of sex hormones can caused AE (reduced BMD and hot-flashes) - mainly for endometriosis

After how many weeks does the eventual decrease in sex hormones happen with GnRH agonists?

2-4 weeks

How can you prevent problems with GnRH agonists?

Use add-back therapy (sex hormones)

What are common choices for add-back?

Progestin-only (norethindrone)
Progestin + estrogen (norethindrone + ethinyl estradiol)
caution with estrogen bc can block effect looking for

What is the mechanism of action for GnRH antagonists?

Competitive inhibition of GnRH receptors

What are delivery forms for GnRH antagonists, and what is the ending of the name for each form?

SC injection "-relix" (peptides)
Oral "-golix" (small molecules)

What is the difference for GnRH antagonists and agonists?

1. no initial surge in sex hormones (no flare w/ cancer)
2. inhibition is not all or nothing (titration is key for desired effect)

What are natural sources of gonadotropins?

postmenopausal urine (menotropins, urofollitropins)
pregnant female urine (natural hCG) - tested w/ pregnancy test

What are examples of gonadotropins?

Menotropins (FSH + LH)
Urofollitropins (FSH)
Follitropin (FSH)
Chorionic gonadotropin (hCG)

What are example indications for gonadotropin therapy?

Controlled ovarian stimulation
Spermatogenesis
Ovulation induction (hCG)

Name some recombinant sources of gonadotropins?

Follitropin ALFA*
Follitropin BETA*
recombinant hCG

made by cultured cells in the lab

Are recombinant sources of gonadotropins the same as natural sources of gonadotropins?

No! they are biosimilars

What is the mechanism of action for gonadotropins?

Activate LH and FSH
stimulate gonadal stimulation

Where does hCG come from?

placenta

How are gonadotropins administered?

SC injection

Name adverse effects of gonadotropins

nausea, cramps
breast tenderness
ovarian enlargement --> ab pain
blood clots (increases E2 estradiol)
multiple births
promote growth of hormone-sensitive cancers

How are gonadotropins (hCG) abused?

for weight loss
body building --> decrease fat while increase muscle

What are anabolic effects of steroid (hCG) use for body building?

testicular atrophy --> hypogonadism
gynecomastia

Name examples of estrogen agonists

estradiol*
estradiol cypionate
conjugated estrogens
ethinyl estradiol
menstranol

What are indications for estrogen therapy?

Low estradiol (primary ovarian insufficiency)
post-menopausal HRT
Oral contaception
Feminizing hormone therapy
Cancer therapy

Name some progestin agonists

Progesterone
Levonorgestrel, Norgestimate (BC)

What are indications for progestin agonists?

Post-menopausal HRT
oral contraceptive
feminizing hormone therapy

Name some examples of androgen agonists

Testosterone
Testosterone isocaproate
Methyltestosterone

What are indications for androgen agonists?

Low T - lab confirmed
Masculinizing hormone therapy
Cancer treatment

Are ester estrogens active drugs and what makes them this way?

No - they're prodrugs
17-OH -->must be removed prior to activity
ex. estradiol cypionate

Are sulfate estrogens active and are they made that way?

no prodrugs ---> enzymatic activation
Natural forms (horse urine)

Name the forms of estrogen therapy that are prodrugs

estradiol cypionate
estrone sulfate
equillin sulfate
mestranol

Name active forms of estrogen therapy

estradiol
ethinyl estradiol

Why are synthetic analogues of gonadotropins better?

more predictable ADME

which form of progestin therapy needs to be enzymatically acted upon to become activated?

ester progestins
ex. norgestimate

What are synthetic analogues of progestins commonly used for?

HRT
Contraception

Is progestin therapy given orally or injected?

orally

What type of progestin is more commonly used? (ester or synthetic)

synthetic analogues

What two types of androgen agonists that have a methyl group at the 17th position?

sulfates and synthetic analogues
improves resistance to metabolism

which type of androgen agonist are pro drugs?

Esters - given by IM injection
ex. testosterone isocaproate and testosterone sulfate

What androgen agonists are naturally found in blood and urine?

sulfates
rarely used as drugs

Name androgen agonists

Testosterone
Testosterone isocarpoate
Testosterone sulfate
methyltestosterone

Give an example of an anti-estrogen or sex hormone antagonist?

Fulvestrant

What is the indication for anti-estrogen therapy?

Breast cancer

What is an example of anti-progestin therapy?

Mifepristone

What is an indication for anti-progestin therapy?

Pregnancy termination (abortion)

What are examples of anti-androgen therapy?

Spironolactone*
Bicalutamide*
Flutamide
Apalutamide

What are indications for anti-androgen therapy?

Prostate cancer (-lutamide)
Acne vulgaris (sprionolactone) females w/ acne
PCOS (sprionolactone) change size of cysts

What is the common ending for anti-androgen therapies?

lutamide

What drug is an estrogen receptor antagonists?

Fluvestrant

What does Fluvestrant do to the estrogen receptor?

increases receptor degradation
"selective estrogen receptor degrader" - SERD

What is fluvestrant treat?

hormone-sensitive breast cancers

What drug is a progesterone receptor antagonist?

Mifepristone

What sex hormone is critical in pregnancy and often supplemented

maintain pregnancy

What is Mifepristone used for?

termination of pregnancy

What drug is an antagonist at both androgen and mineralcorticoid receptors?

Spironolactone

What is Spironolactone used for anti-androgen wise?

PCOS
acne
feminizing hormone therapy

Name a non-steroid anti-androgen drug

Bicalutamide

What is the mechanism of action for non-steroid anti-androgen drugs?

act as competitive inhibitors at AR
highly selective for AR

What is the main indication for non-steroid anti-androgen drugs?

Prostate cancer

What does SERM mean?

selective estrogen receptor

Name some SERMs

clomiphene
Raloxifene
Tamoxifen*
Toremifene
Ospemifene
Bazedoxifene

What kinds of conditions is SERM therapy indicated?

Fertility therapy (clomiphene)
Vaginal dryness (ospemifene)
Osteoporosis (raloxifene*, bazedoxifene)
Breast cancer (tamoxifen, toremifene)

What does SPRM mean?

selective progestin receptor modulator

What is the drug that is a SPRM?

Ulipristal Acetate

What is an indication for SPRM treatment?

Emergency contraception (abortion)
Uterine fibroids (leiomyomas)

What does SARM mean?

Selective androgen receptor modulator

What is an example of a SARM?

No.
bc men DoNt nEed bIrThConTrol tHeY'rE so ReliAblE
could be used for OP, BPH, and prostate cancer
okay so fuck women here

What is the mechanism for selective receptor modulators?

Activate or inhibit different tissues
dependent on co-activators/repressors

What tissues are SERMs estrogenic in?

endometrium
vasculature
bone (OP)

What are SERMs non-estrogenic in?

breast
hypothalamus

What is the active form of tamoxifen and what is it metabolized by?

Endoxifen
CYP 2D6 & 3A4

Because tamoxifen is a non-steroid SERM it is a ______?

prodrug

What are the AE from anti-estrogenic tissues from SERM therapy?

Hot flash - hypothalamus
muscle cramps - extremities
vaginal dryness (mini-menopause)

What are the AE from estrogenic tissues from SERM therapy?

Blood clot risk (DVT/PE)
endometrial proliferation, bleeding, uterine cancer

What delivery forms are SERMs available in?

oral

What delivery forms are SPRMs available in?

oral

What needs to happen to ulipristal acetate before it is active?

acetate removed enzymatically
prodrug
synthetic analogue

What tissues do SPRMs effect?

progesterone-sensitive tissues