20: Pharmacology of the HPG Axis

Leuprolide

Gonadorelin

Histrelin

GnRH Agonists (end in -relin)

MOA

• Pulsatile → increased LH + FSH

• Sustained release turns off GnRH → decreased LH + FSH → hypogonadism

  • When starting sustained release → initial LH + FSH flare before they turn off

• Leuprolide → more potent than endogenous GnRH for pituitary stimulation

  • May produce testosterone flare 

USE

• Short acting → ovulation stimulation & manipulation for IVF

• Endometriosis, breast cancer, palliative treatment of advanced prostate cancer

• Gonadorelin → evaluating hypothalamic-pituitary gonadotropic function

AE

• Hot flashes, gynecomastia, osteoporosis, decreased libido

• VTE (gonadorelin, leuprolide with pulsatile dosing or at initiation of SR)

CI

• Hypersensitivity to GnRH or analogs

• Pregnancy

• Lactation

Degarelix

Aberelix

GnRH Antagonists (end in -relix)

MOA

• Blocks GnRH receptor → immediate drop in FSH + LH secretion → blocks ovulation

• Degarelix → GnRH antagonist → immediate drop in testosterone (NO flare)

USE

• Degarelix → advanced prostate cancer

AE

• Ovarian hyperstimulation, nausea, headache

CI 

• Pregnancy + lactation

• Vaginal bleeding (unknown cause)

• Ovarian cysts, primary ovarian failure, thyroid/adrenal dysfunction 

DI

• Exogenous gonadotropins may need to be adjusted when using these

Ethinyl Estradiol

Mestranol

Oral estrogens (synthetic)

Estrogen Replacement Therapy/Estrogen Agonists

USE

• Vasomotor symptoms of menopause (hot flashes/flashes)

• GU syndrome of menopause (vaginal/vulvar atrophy)

• Prevention of osteoporosis

• MUST combine with progesterone if uterus is intact → avoids endometrial cancer 

AE

• Thromboembolism, category X in pregnancy, endometrial/uterine/breast neoplasia

• Nausea, headache, breast tenderness, heavy menstrual bleeding, fluid retention

NOTES

• Boxed warnings

  • Not for CHD prevention

  • May increase risk of dementia

  • Estrogen replacement without progestin replacement may increase risk of endometrial cancer in women with intact uterus

CI

• Medical history of/current VT, recent (~1 year) arterial thrombosis (MI, stroke)

• Breast cancer or endometrial cancer

• Estrogen-dependent tumor

Clomiphene

Selective Estrogen Receptor Modulators (SERMs)

MOA

• Blocks estrogen Rs in pituitary → decreased negative feedback → increased LH + FSH 

USE 

• Induce ovulation in anovulatory infertility (agonist in ovaries) 

  • Given days 5-9 of cycle, ovulation day ~15

AE

• Multiple follicular growth (pregnancies), hot flashes, mood swings, ovarian hyperstimulation (rare)

Tamoxifen

SERM

MOA 

• Antagonist in breast

• Agonist in endometrium + bone

• Prodrug activated by CYP2D6 (if 2D6 inhibited → tamoxifen efficacy decreased)

USE

• ONLY SERM approved for treatment + prevention of hormone responsive breast cancer

• Prevents osteoporosis in breast cancer patients

• Administered no more than 5 years to minimize risk of endometrial cancer 

AE

• Hot flashes, mood swings, vaginal bleeding, increased VTE, increased endometrial hyperplasia + cancer

Raloxifene

SERM

MOA 

• Partial agonist in bone

• Antagonist in breast

USE

• Prevent + treat osteoporosis

• Prevent breast cancer risk

AE

• Hot flashes, mood swings, increased VTE, NO risk of endometrial cancer

CI

• Pregnancy + lactation

• VTE history

Fulvestrant

Selective Estrogen Receptor Downregulators (SERD)

MOA 

• Pure estrogen receptor antagonist (downregulator) in all tissues

USE

• Treat breast cancer that has developed resistance to tamoxifen

AE

• Anti-estrogen effects → increased osteoporosis risk

• Headache 

• Pregnancy category D

Anastozole

Exemestane

Aromatase Inhibitors

MOA

• Anastrozole → competitive aromatase inhibitor

• Exemestane → irreversible steroidal aromatase inhibitor

USE

• Postmenopausal breast cancer treatment

• Off-label risk reduction

• No uterine cancer/VTE risk (unlike SERMs)

AE

• Fatigue, arthralgia, vaginal atrophy, increased fracture risk, hot flashes, headache

Testosterone

Androgen Agonist

EFFECTS

• Libido, aggression, acne, oily skin, increased muscle + bone density, spermatogenesis, male genitalia, prostate growth

AE

• Acne, oily skin, erythrocytosis, prostate cancer risk, infertility, aggression, dependence, transdermal absorption risk

Finasteride

5a-Reductase Inhibitor

MOA

• Decreased conversion of testosterone → DHT

USE

• Benign prostate hyperplasia (BPH), male pattern baldness

AE

• Decreased libido, sexual dysfunction, gynecomastia, pregnant women should not handle these tablets → harm to exposed fetus (semen or via transdermal)

Bicalutamide

Flutamide

Androgen Receptor Agonist

MOA 

• Block androgen receptor (testosterone + DHT effects)

USE

• Prostate cancer

• Combined with leuprolide to prevent testosterone flare

Spironolactone

Androgen & Aldosterone Antagonist

MOA

• Increases peripheral conversion of testosterone → estradiol

• Displaces estradiol from SHBG → increases free estradiol = estrogenic effects

Eplerenone

Androgen & Aldosterone Antagonist

MOA

• More selective aldosterone antagonist

• Lower incidence of estrogen-related effects