SERMs, SERDs, Aromatase Inhibitors, & Drugs Used in Infertility

What types of non-steroidal SERMS have tissue selective action?

1. Tamoxifen

2. Raloxifene

3. Tormifene

4. Clomiphene (or antiestrogen according to G & G)

What are the benefits of Selective Estrogen Receptor Modulators (SERMs)?

- act as agonists to produce beneficial estrogenic effects

- act as antagonists to prevent deleterious estrogenic effects on others

Where does Tamoxifen act as a potent estrogen antagonist?

breast cancer cells thus, useful in ER +/ PR+ breast cancer

Where does Tamoxifen act as a partial agonist?

Uterus: endometrial proliferation (increases risk of cancer)

Bone: improves density

Pituitary: lowers FSH/LH and PL

Liver: decreases LDL (no change in HDL or TG) and increases DVT risk

Where does Raloxifene act as a partial agonists and what is the effect?

ER in bone causing a dose dependent ↑ in osteoblastic and ↓ in osteoclastic activity

Where does Raloxifene act as an ER antagonist?

Endometrium: no risk of cancer

Breast: reduces cancer risk

Liver: decreases LDL (no HDL or TG) and increases thromboembolism

What is the primary clinical use of Raloxifene?

postmenopausal osteoporosis

What are the adverse effects of SERMS?

hot flashes, arthralgia, leg cramps

What are the contraindications to SERMS?

women at higher risk of thromboembolism

What are Selective Estrogen Receptor Degraders (SERDs)?

Pure ER antagonist; no estrogenic effects

What is the mechanism of action of SERDs?

causes ER to be ubiquitinated and undergo protosomal degradation

What is an example of a SERD?

FulvestRant (Full estrogen Receptor antagonist)

What is the clinical use of SERDs?

post-menopausal tamoxifen resistant ER+ breast cancer

What are the types of nonsteroidal (reversible) aromatase inhibitors?

anastrozole, letrozole, vorozole

What are the types of steroidal (irreversible) aromatase inhibitors?

exemestane

What is the mechanism of action of aromatase inhibitors?

Inhibits the CYP enzyme responsible for aromatization of androgens to estrogens

Which hormone conversions do aromatase inhibitors target?

- testosterone to estradiol

- androstenedione to estrone

Where are aromatase inhibitors most active?

peripheral tissues of post-menopausal women

What are the clinical uses of aromatase inhibitors?

- ER+ breast cancer in post-menopausal women

- follow up after tamoxifen use for 2-5 years

- precocious puberty

What are the adverse effects of aromatase inhibitors?

hot flashes, osteoporosis, vaginal dryness, and hair thinning

What is an advantage of aromatase inhibitors?

does not ￪ the risk of uterine cancer or venous thromboembolism

What are the disadvantages of aromatase inhibitors?

lack the beneficial effect of maintaining BMD; thus, given with bisphosphonates to decrease osteoporosis

What is the mechanism of action of Clomiphene?

Effectively inhibit the negative feedback effect of E2 on hypothalamus/pituitary

What are the physiologic effects of Clomiphene?

- Increased secretion of gonadotropins (FSH/LH) and estrogens

- Follicular maturation and ovulation

What is the clinical use of Clomiphene?

anovulation in an intact hypothalamic-pituitary-ovarian axis and adequate estrogen production

What are the adverse effects of Clomiphene?

multiple pregnancies, reversible hot flashes, ovarian enlargement, and visual disturbances

What are the types of synthetic GnRH analogs?

leuprolide and 'relins'

What is the mechanism of action of GnRH agonists on continuous administration?

Cause a transient stimulation of FSH/LH release f/b downregulation of the GnRH receptor and inhibition of FSH/LH secretion

What are the clinical uses of leuprolide and depot GnRHs?

- pharmacological castration in GnRH-dependent precocious puberty in children

- hormone responsive conditions (cancers, fibroids, endometriosis)

- prevents premature LH surge in women undergoing ART*

What are the adverse effects of GnRH agonsits?

hot flashes, vaginal dryness, osteoporosis, weight gain, decreased libido, testicular atrophy, erectile dysfunction

What is the mechanism of action of GnRH agonists on intermittenet administration?

stimulate FSH secretion in ART to facilitate follicle development and ovulation induction with hCG

How are Intermittent GnRH agonists administered?

low-frequency pulses (1/90 min) during the follicular phase

What are the types of GnRH Antagonists?

Ganirelix, Cetrorelix, Degarelix

What is the mechanism of action of GnRH Antagonists?

reversibly and competitively suppresses LH surge to prevent premature ovulation stimulation and immediately decrease gonadotropin secretion

What are the clinical uses of Ganirelix and Cetrorelix?

same as leuprolide depot injections under ART protocols

What is the clinical use of Degarelix?

advanced prostate cancer

What is the mechanism of action of Danazol?

Suppresses mid-cycle FSH/LH surge causing anovulation, endometrial atrophy, and amenorrhea over a few weeks

What is a primary use of Danazol?

Endometriosis

What are the adverse effects of Danazol?

acne, hirsutism, reduced breast size, deepening of voice, edema and weight gain