SERMs and Androgens

SERMs

Selective estrogen receptor modulators

tamoxifen, toremifene

Agonists at bone, antagonists at breast

Agonists at endometrium

Tx metastatic breast cancer in women (10-20mg/day)

Raloxifene, bazedoxifene

Agonists at bone, antagonists at breast

Antagonists at endometrium

Prevent osteoporosis in postmenopausal women

Common side effects of SERMs

Menopause-like symptoms: hot flashes, vaginal dryness, mood swings, fatigue

Increased risk of blood clots

Ospemifene

A SERM share a core structure with tamoxifen

Indications: moderate or severe dyspareunia. And vaginal dryness, due to menopause

Clomiphene

Classified as an antagonist or partial agonist

Block estrogen’s negative feedback inhibition on FSH/LH secretion

Increased LH and FSH for ovulation induction

Approved for treating infertility in anovulatory or oligo-ovulatory women

SERMs as ER agonists in bone

Specificity of SERMs action depends on the selective expression of cofactors for estrogen receptors (ER) in different tissues

• binding of SERMs or estradiol induce different conformations of the ER

• Specific cofactors in different tissues confer selectivity of SERMs

SERMs: MOA of agonists and partial agonists in bone tissue

SERMs: MOA of full agonists and antagonists. In breast tissue

testosterone production

Main androgen

Production in males:

• 95% by Leydig cells in testis

• 5% by the adrenal

• Like other steroids, the majority binds to plasma proteins

Testosterone effects

Promote general growth and growth of reproductive organs during puberty

Secondary sex characteristics: virilization

Anabolic effects

• increased synthesis and decreased breakdown of proteins

Feedback regulation of androgens (hypothalamus and pituitary)

DHT (Dihydrotestosterone)

More potent at androgen receptors than testosterone

Testosterone: therapeutic uses

Main use: male hypogonadism

• orally administered testosterone mostly inactivated by the liver

• More often used: conjugated esters, alkylated derivatives (depo-testosterone: testosterone cypionate in oil)

Testosterone: adverse effects

Exogenous testosterone suppresses testicular activity due to inhibition of gonadotropin release, azoospermia, decreased size of the testis

Hepatotoxicity (more with 17-alkylated analogs)

• increased liver enzymes, cholestasis (decreased bile flow from liver), liver tumor, vascular changes

Danazol

Androgen receptor agonist

Also has weak progestational and glucocorticoid activities

Suppresses ovarian function and inhibits mid-cycle surge of LH/FSH

Major use: Tx endometriosis

• AE: weight gain, acne, increased hair growth

• Contraindications: pregnancy, hepatic dysfunction

Synthetic androgen receptor antagonists

Flutamide, bicalutamide, darolutamide, enzalutamide

Newer drugs (bica-, daro-, enza-)generally have less adverse effects including liver toxicity

Eg Daro- SE: fatigue, bone fracture, fall

These drugs are often combined with GnRH agonists or antagonists to treat prostate cancer

Flutamide: structure and uses

Off-label uses: hirsutism, PCOS, female pattern hair loss

AE: hepatic injury, need blood monitoring of liver function gynecomastia (about 9%)

Clascoterone (winlevi)

Synthetic androgen receptor (AR) antagonists

Approved by FDA in 2020 for treating acne

• androgens stimulate secretion of sebum, which contribute to acne

• As and AR antagonist, the drug decreases sebum production

• Topical cream, little systemic absorption

AE: local irritation, may suppress hypothalamic-pituitary-adrenal axis

Androgen receptor antagonists

Flutamide, Daro-, Enza-, Bica-lutamide: prostate cancer

Spironolactone: hirsutism in women

Clascoterone: acne

5 alpha-reductase inhibitor

Finasteride (Proscar 5mg, Propecia 1mg)

DHT is more potent at androgen receptors

Tx BPH, male pattern hair loss

AE: decreased libido, ED, breast tenderness

Inhibits formation of testosterone into DHT by 5 alpha-reductase