elsaid - hormonal agents

steroidogenesis

• hypothalamus — releases GnRH which acts on the GnRH receptor on the anterior pituitary gland

• anterior pituitary gland — releases FSH and LH

  • FSH and LH acts on the receptors on the ovaries and testes

• ovaries — produces estrogens and progestins

• testes — releases testosterone

  • aromatase metabolizes testosterone into estrogens

  • 5-alpha reductase metabolizes dihydro-testosterone

the principal estrogenic hormone

17β estradiol (E₂)

• synthesized by aromatization of testosterone in the ovaries and other tissues

• mediates its effect via two types of receptors ER_𝜶 and ER_β (both are nuclear receptors; i.e. transcription factors)

E2

binding of the E₂ (an ER agonist) to ER results in dimerization of the receptor and recruitment of co-activator proteins

the chromatin network opens up and transcription of target genes is initiated

estrogen antagonist

bind to ER resulting in dimerization of the receptor and recruitment of co-repressors and other protein that result in inhibition of transcription of target genes

E2 in ER+ cell results in:

• enhanced cellular proliferation

• increase in angiogensis

• reduction in apoptosis

• estrogen was also shown to induce growth factor-induced activation of Human Epidermal Receptor family

Selective Estrogen Receptor Modulators

Tamoxifen, Raloxifene, and Toremifene

• indicated for prevention of breast cancer in high-risk individuals and as adjuvant treatment in ER+ breast cancer in pre AND post menopausal females

• acts as an antagonist in breast cancer cells

  • binding to ER results in dimerization and recruitment of corepressors that prevent gene transcription

• resistance is due to the recruitment of coactivators in Tamoxifen-bound ER

• ADEs: vasomotor symptoms, increased risk of stroke, DVT, and endometrial cancer

tamoxifen metabolic pathway

• tamoxifen is metabolized by a combination of CYP3A4 and CYP2D6 to generate Endoxifen

• compared to Tamoxifen, Endoxifen has significantly higher binding affinity to ER_𝜶 and ER_β and results in ER degradation

• the question whether the clinical efficacy of Tamoxifen is impacted by CYP2D6 genotype is a focus of investigation

fluvestrant

SERD — Selective Estrogen Receptor Downregulator/Degrader

• binding of Fluvestrant to estrogen receptor prevents receptor dimerization and binding to estrogen response element and gene transcription

  • instead the Fluvestrant-bound ER is degraded

• advantages:

  • is effective in situations of Tamoxifen resistance

  • reduces ER levels in the cancer cell

  • acts a pure antagonist

  • adverse effects include vasomotor symptoms (hot flashes)

distribution and funciton of aromatase

• expression:

  • in multiple tissues and organs including ovaries, urogenital, brain, heart, blood vessels, breasts, and adipose tissue

• pre-menopause:

  • ovarian aromatase is responsible for the majority of E₂

  • ovarian aromatase is regulated by LH

    • increasing circulating LH leads to increasing aromatase expression

• post-menopause:

  • circulating E₂ is produced by aromatase in adipose tissue, adrenal gland, and in muscles

  • aromatase in these tissues is NOT regulated by LH

aromatase inhibitors

aminoglutethimide, exemestane, anastrozole, and letrozole

• causes a reduction in circulating estrogen levels

• indicated in early and advanced ER+ best cancer in postmenopausal females

  • can only be given in premenopausal females after ovarian ablation

type 1 aromatase inhibitors

exemestane

• third generation

• steroidal irreversible inhibitor of aromatase

type 2 aromatase inhibitors

• aminoglutethimide

  • first generation

  • NON-steroidal reversible inhibitor of aromatase

• anastrozole

  • third generation

  • NON-steroidal reversible inhibitor of aromatase

• letrozole

  • third generation

  • NON-steroidal reversible inhibitor of aromatase

aromatase inhibitor class effects

• hot flashes

• arthralgia, pain

• osteoporosis, fracture risk

• depression

*estrogens and androgens inhibit bone resorption (via inhibiting osteoclast function) and stimulate bone formation

androgen deprivation therapy (ADT)

• GnRH stimulates anterior pituitary to release FSH and LH —> testosterone

• GnRH analogs:

  • initially stimulate FSH and LH release

  • sustained exposure to GnRH analogs results in desensitization of GnRH receptor

  • formulated as depots to allow sustained exposure to the drug

• GnRH antagonists:

  • binds to the GnRH receptors and prevents GnRH from binding and suppression of FSH and LH release

androgen deprivation therapy (ADT) — ADEs

• hot flashes

• decreased libido

• osteoporosis

• weight gain and loss of muscle mass

• fatigue and anemia

GnRH analogs

• Leuprolide

• Triptorelin

• Goserelin

• Histrelin

GnRH antagonists

Degarelix

combined androgen blockade

using both GnRH analogs and antagonists

• analogs cause initial flare-up (bc of initial increase in GnRH receptor stimulation)

  • overtime —> reduces androgen synthesis

• antagonists does NOT cause flare-ups —> solves initial flare-up

first-generation antiandrogens

(aka conventional antiandrogens)

Flutamide, Bicalutamide, Nilutamide

• MOA: bind to AR and prevents androgens from binding to the AR

• downstream effect: reduce androgen-dependent prostate cancer cell proliferation

• an established mechanisms of resistance is the anti-androgens having agonist-like properties (increase prostate cancer cell proliferation)

mechanisms of resistance to ADT

1. more androgens are synthesized and released by the adrenal gland

2. AR activated by corticosteroids

3. AR activated growth factors

4. AR amplification

5. AR mutations

second-generation antiandrogens

Enzalutamide

• acts as a pure antagonist — LACKS partial AR agonist activity that occurs with bicalutamide resistance

• higher binding affinity to AR compared to first-generation agents

inhibitors of steroidogenesis

inhibitors of steroidogenesis inhibit androgenic hormone synthesis in the adrenal cortex

e.g. Ketoconazole and Abiraterone

• MOA: inhibition of key enzymes in the biosynthetic pathway of androstenedione (which is converted to testosterone)

• both ketoconazole and abiraterone are given with prednisone for patients with advanced metastatic prostate cancer

  • ketoconazole and abiraterone inhibit cortisol biosynthesis and thus patients require exoggenous corticosteroid supplementation

• abiraterone is more potent compared to ketoconazole