Hormone Therapy in

Oncology – Females
Dr Sumayya Latif
 Estrogen
• 18-C steroid
• Testosterone-19-C ring, 1 Carbon removed and we
get estrogen
• Steroid in nature
 Hormone Synthesis
• Sex hormones are steroid hormones and hence their synthesis takes
place from cholesterol which is converted to Pregnenolone by
Desmolase.
• It then forms androgens DHEA, Androstenidione and Testosterone.
• Testosterone can form Dihydrotestosterone by action of 5-alpha
reductase or estradiol by the action of aromatase.
• Aromatase also catalyzes conversion of androstenidione to Estrone
which can be further converted to estradiol.
• Steroid hormone synthesis taking place in varying degrees in the
adrenals, Leydig cells (testes) and Theca & granulosa cells (ovaries).
• Like the granulosa cells, adipose cells also contain Aromatase and are
hence involved in androgen conversion into estrogen.
 Hormone MOA
• Like all steroid homones, the sex hormones enter the cell and interact
with their specific receptor located inside the nucleus.
• Estrogen receptor = ER
• Androgen receptor = AR
• Progesterone receptor = PR
• The receptor upon activation undergoes dimerization with another
activated receptor.
• The dimer interacts with specific DNA sequences (elements = ARE and
ERE) activating their transcription and subsequent translation.
• Hence new proteins are formed. These proteins may
• stimulate cell growth (e.g. growth factors) or
• they may inhibit cell death.
• If these receptors are being expressed by tumor cells then such tumors
are hormone-dependent and the activation of these receptors would
lead to tumor proliferation.
 Anti-estrogens
• SERMS
• Estrogen Antagonists
 SERMS (Selective estrogen
receptor modulators)
• MOA
• Competitively bind to the estrogen receptor (ER) and decrease
their activation by
• Decreasing dimerization
• Decreasing binding of estrogen to ER
• Act as selective estrogen receptor modulators; i.e.
• Act as estrogen antagonist in the breast via inactivation of AF2
domain on ESR-1
• Act as estrogen agonist in the endometrium and bone since AF1 on
ESR-1 domain still functional
• Stimulates secretion of transforming growth factor-β (TGF-β):
which then acts to inhibit expression and/or activity of TGF-α and
IGF-1, two genes that are involved in cell growth and
proliferation.

• Cell cycle–specific agent that blocks cells in the mid-G1-phase

of the cell cycle. Effect may be mediated by cyclin D.
 MOR
• Decreased expression of ER.
• Mutations in the ER leading to decreased binding affinity to
tamoxifen
• Cross talk: Overexpression of growth factor receptors such as as
EGFR, HER2/neu, IGF-1R or TGF-β that counteract the inhibitory
effects of tamoxifen by estrogen receptor signaling and activation.
• Presence of ESR1 mutations: A conformational change in ligand-
binding domain that mimics conformation of activated ligand-bound
receptor and generates constitutive, ligand-independent
transcriptional activity, resulting in resistance to hormonal therapy
• Dysregulation of cell cycle
• Co-activator/co-repressor (ERE) imbalance
 Pharmacokinetics
Absorption
• Lipophilic, good bioavailability
• Rapidly and completely absorbed in GI tract.
• Peak plasma levels: achieved within 4–6 hours after
oral administration.
Distribution
Distributes to most body tissues, especially in those
expressing ER. Present in very low concentrations in
CSF. Nearly all of drug is bound to plasma proteins.
 Pharmacokinetics
Metabolism
• Extensively metabolized by liver cytochrome P450 enzymes
(CYP3A4,CYP2D6) after oral administration.
• Main metabolites:
1. N-desmethyl tamoxifen
2. 4-OH tamoxifen
3. 4-OH N-desmethyl tamoxifen (Endoxifen)—most important
metabolite
Then, further metabolized to inactive form
Excretion
Tamoxifen and its metabolites: primarily (75%) in feces with
minimal clearance in urine.
 Indications
1. Used in both premenopauasal and postmenopausal women with
hormone dependent breast cancer (ER: +ve, PR: +ve, ER, PR:+ve)
• Early-Adjuvant
• Locally advanced: Neoadjuvant/adjuvant
• Metastatic: 1st line

2. Chemoprevention:
• DCIS: after treatment given as chances of C/L breast involvement

3. Approved as a chemopreventive agent for women at high risk for

breast cancer. “High-risk” women are defined as women >35 years
and with a 5-year predicted risk of breast cancer ≥1.67%, according
to the Gail model.
Generally hormone therapy is not given concurrently with
chemotherapy or radiotherapy.
Allred Scoring Method
 Dosage
• Tamoxifen (Nolvadex)
• PO, 10 mg BD; up to 5 years
 Side effects
1. Endometrium:
• Associated with an increased risk of endometrial
hyperplasia, polyps and endometrial cancer.
• Patient should notify menstrual irregularities, abnormal
vaginal bleeding and pelvic pain and/or discomfort
• Routine follow-up with a gynecologist, Pelvic exam, USG
2. Coagulation System:
• Thromboembolic complications including deep vein
thrombosis, pulmonary embolism and superficial phlebitis.
• Incidence of thromboembolic events may be
increased when given concomitantly with chemotherapy
3. Ophthalmic side effects
• Visual disturbances including cataracts, retinopathy and
decreased visual acuity
 Side effects
4. Vasomotor changes
• In skin, increase NO , hot flashes
5. Water retention, Peripheral edema
6. Cardiovascular :
• Lipid metabolism: increase HDL, decrease LDL, decrease
cholesterol, increase triglycerides
7. Analytical thinking decrease
8. Carcinogenicity: Endometrial ca, HCC
9. Cholestasis: Gall stones, jaundice, Itching
10. Teratogenic: birth control advice
11. Gen. Reproductive tract: Ovarain cysts
 Good Effects
• Decreases cholesterol and cardiovascular
mortality
• Prevents osteoporosis by preventing decline
in bone mineral density
 Drug Interactions
• Warfarin-Tamoxifen can inhibit metabolism of warfarin by liver P450
system leading to increased anticoagulant effect.
• Erythromycin, calcium channel blockers and cyclosporine: Metabolized by
liver P450 system. Tamoxifen and its metabolites are potent inhibitors of
hepatic P450 enzymes and may inhibit the metabolism of various drugs,
including e.
• Cyclophosphamide: Inhibit its metabolic activation as utilizing liver P450
system pathway for activation
• Antidepressants - selective serotonin reuptake inhibitors (SSRIs) or
selective noradrenergic reuptake inhibitors (SNRIs) : paroxetine, fluoxetine,
bupropion, duloxetine and sertraline, Antipsychotics - thioridazine,
perphenazine, and pimozide, Drugs such as cimetidine, quinidine,
ticlopidine and terfenadine are inhibitors of CYP2D6, which can then
interfere and inhibit tamoxifen metabolism resulting in lower blood levels
of the active tamoxifen metabolites.
 Toremifene
• Similar to Tamoxifene
• Tamoxifene resistance cause its resistance
• HCC incidence less
• Role in metastatic breast carcinoma

Raloxifene
• Tamoxifen is superior to raloxifene in terms of both invasive and non-
invasive cancer events but was associated with a higher risk of
thromboembolic events and endometrial cancer
• Agonist effect on endometrium is minimal, less endometrial hyperplasia,
less chances of malignancy
• Role in chemoprevention
 Aromatase
• Aromatase is the enzyme complex responsible for the final step in
estrogen synthesis via conversion of androgens, androstenedione and
testosterone to estradiol and estrone.
• Synthesis of ovarian hormones ceases at menopause.
• Source of aromatase is ovary in pre-menopausal ladies
• Post-menopausal: adrenals and adipose tissue, some from muscle,
breast and breast tumor tissue
• So, estrogen continues to be converted from androgens (produced by
the adrenal glands) by aromatase, an enzyme of the cytochrome P450
(CYP) superfamily.
• This pathway was used to develop anti-aromatase class of compounds.
• Aromatase (cytochrome P450 19 [CYP19]) is encoded by the highly
polymorphic CYP19 gene.
 Aromatase Inhibitors

Nonsteroidal (Type-2)
Steroidal (Type-1)

Exemestane

1st Generation 2nd Generation 3rd Generation

Aminoglutethimide Rogletimide Anastrozole
Fadrozole Letrozole
 Steroidal
• Exemestane (Aromasin)
• MOA
• Irreversibly bind to aromatase enzyme and inhibit
estrogen synthesis, also known as an aromatase
inactivator due to its irreversibly binds with and
permanently inactivates the enzyme.
• Inhibits the synthesis of estrogens by inhibiting conversion
of adrenal androgens (androstenedione and testosterone)
to estrogens (estrone, estrone sulfate and estradiol)
• No inhibitory effect on adrenal corticosteroid or
aldosterone biosynthesis.
 MOR
• Some degree of cross-resistance exists between
exemestane and non-steroidal aromatase inhibitors
• Activation of growth factor signaling pathways,
specifically HER2 and IGF1-R, with cross-talk with
the ER signaling pathway, estrogen receptor
signaling and activation.
• Co-activator/co-repressor imbalance
• CYP-19 gene overexpression lead to aromatase to
be more active
 Pharmacokinetics
Absorption
• Excellent bioavailability via oral route
• Absorption is not affected by food.
Distribution
• Widely distributed throughout body.
• About 90% - bound to plasma proteins.
Metabolism
• Extensively metabolized in liver by CYP3A4 enzymes (up to 85%) to
inactive forms.
• Major route of elimination: Hepatobiliary with excretion in feces
• Only 10%: Renal excretion
 Indications
• Treatment of advanced breast cancer in post-
menopausal women whose disease
has progressed following tamoxifen therapy.

Dose
25 mg PO once daily after a meal.
 Adjuvant Endocrine Therapy for
Premenopausal Breast Cancer
Suppression of Ovarian Function Trial (SOFT) & the Tamoxifen and
Exemestane Trial (TEXT) trials
Tamoxifen vs tamoxifen + GnRH analogue vs Exemestane + GnRH
analogues
DFS, OS: increase in last category
Tamoxifen + ovarian suppression VS Exemestane + ovarian suppression
Aromatase inhibitor, exemestane is more effective than tamoxifen in
preventing breast cancer recurrence in young women who also receive
ovarian function suppression
 Toxicities
1. Arthralgias & myalgias.
2. Hot flashes
3. Mild nausea.
4. Fatigue.
5. Headache.
6. Weak androgenic properties - Use at higher doses has been
associated with steroidal-like side effects, such as weight gain, acne,
loss of hair on scalp, hypertrichosis. However, these side effects
have not been observed with FDA-approved dose (25 mg per day).
7. Osteoporosis:
Type-2 > Type1 > Tamoxifen
 Nonsteroidal
• Generations:
• First
• Aminoglutethamide: non-selective in its action; i.e., it leads to
inhibition of all adrenal steroids.
• Second
• Rogletimide, Fadrozole: not in current clinical use.
• Third
• Anastrozole (Arimidex, Aromatraz)
• PO: 1mg OD can be used up to 5 years
• Letrozole (Femara, Letara)
• PO: 2.5mg OD, can be used up to 5 years
 MOA

• Reversibly bind to aromatase enzyme at androgen

binding site, thus inhibiting estrogen synthesis from
androgen. Thus, although ER are present but
circulating estrogens are diminished.
• Serum estradiol levels are suppressed by 90% within
14 days and nearly completely suppressed after 6
weeks of therapy.
 MOR
• Decreased expression of estrogen receptors (ER).
• Mutations in ER leading to decreased binding
affinity to anastrozole.
• Overexpression of growth factor receptors, such as
EGFR, HER2/neu, IGF-1R, or TGF-β that counteract
the inhibitory effects of anastrozole.
• Co-activator/co-repressor imbalance
• CYP-19 gene overexpression lead to aromatase to
be more active
 Contraindication
• Premenopausal women as it would cause
gonadal stimulation. If they are to be
used in this case, then ovarian function
suppression prior to their use is
mandatory.
• Oophorectomy
• GnRH Agonist (Leuprolide)
 Pharmacokinetics
Absorption
• Lipophilic, good bioavailability
• Rapidly and completely absorbed after oral
administration. Food does not interfere with oral
absorption.
Distribution
• Significant uptake in peripheral tissues and in
breast cancer cells.
• Bound to plasma protein-can’t cross BBB
 Pharmacokinetics
Metabolism
Anastrozole
• Extensively metabolized in liver (up to 85%) by N-dealkylation,
hydroxylation and glucuronidation to inactive forms.
• Major route of elimination: Fecal
• Only 10%: Renal excretion
Letrozole
• Occurs in liver by cytochrome P450 system.
• Process of glucuronidation leads to inactive metabolites
• Parent drug and metabolites: Excreted via kidneys with over
75%–90% cleared in urine.
 Indications
1. Metastatic breast cancer—FDA-approved for first-line treatment of
postmenopausal women with hormone-receptor positive or hormone-
receptor unknown disease.
2. Metastatic breast cancer—Postmenopausal women with hormone-
receptor positive, advanced disease, and progression while on tamoxifen
therapy.
3. Adjuvant treatment of postmenopausal women with hormone-receptor
positive, early-stage breast cancer; FDA-approved.
• Non-steroidal aromatase inhibitors are a first line option.
• Steroidal aromatase inhibitors are a second line option.

• Anastrozole vs Letrozole?
• Letrozole more potent
• Hepatic vs renal function
 Side effects
Effects of estrogenic def., already post-menopausal
1. Osteoporosis: susceptibility to fractures especially
if one or more of following factors are present:
• Positive past history e.g.: Radiological findings
• prolonged steroid use
• Premature menopause (before 45 yr.)
• Prolonged secondary amenorrhea (amenorrhoea > 1yr)
• Maternal history positive
• Low BMI
• DEXA Scan: start of therapy and at regular
intervals. Treatment or prophylaxis for osteoporosis
should be initiated when appropriate.
 Side effects
2. Hot flashes
3. Mild musculoskeletal pains and arthralgias: Involving hands,
knees, hips, lower back, and shoulders. Early morning stiffness
is usual presentation - post-menopausal effect
4. Vaginal dryness
5. Dry, scaling skin rash.
6. Headache and fatigue.
7. Mild elevation in serum transaminases and serum bilirubin:
Most often seen in patients with established metastatic
disease in the liver.
8. Thromboembolic events- rarely observed.