Introduction to Hormones in Cancer
The use of hormones in cancer therapy is mainly focused on the blockade of hormones. Hormones can be the contributing cause of cancer. This is because hormones are growth factors, and an increase in hormonal exposure leads to an increase in the risk of cancer.
It is always important to keep in mind that only certain types of cancer are sensitive to hormonal blockage.
Prostate Cancer
The main hormone of concern for prostate cancer is androgen. There are dependent and independent pathways.
The dependent pathway where dihydrotestosterone (DHT) binds to a heat-shock protein, is internalized into the DNA and causes growth. Excessive activity of this pathway can lead to uncontrolled growth.
The independent pathway is also known as the hormone-resistant pathway. The main problems with this pathway are the over-amplification of androgen receptors, the mutated androgen receptor, and the overexpression of Bcl-2. A blockage of androgen or testosterone will not treat this pathway.
Breast Cancer
Breast cancer is considered to be receptor stasis, meaning that it is categorized by (+/-) HER2, (+/-) estrogen receptor, and (+/-) progesterone receptor.
These (+/-)s can determine the type of treatment as well as the prognosis. In most cases, positive receptors tend to have a better prognosis than negatives since we at least how what receptors to target.
Terminology
- Surgical Castration: the reduction of circulating hormones by the removal of the primary source of sex hormone production. (oophorectomy – ovary removal, orchiectomy – testicle removal).
- Medical/Chemical Castration: the reduction of circulating hormones by using chemicals to directly and completely or nearly completely reduce hormone production.
- Androgen-deprivation therapy: the mainstay of prostate cancer therapy. This includes any agent used to reduce physiologic androgens.
Hormone Synthesis Pathways
The pathway always starts with cholesterol molecules.
Step 1: Cholesterol is converted to pregnenolone of the progestagens group. Pregnenolone can either be converted to progesterone or 17a-hydroxypregnenolone.
Step 2a: Pregnenolone is converted to progesterone by 3B-HSD.
- Step 3.1a: Progesterone is converted to deoxy-corticosterone by 21-hydroxylase.
- Step 3.1b: Deoxy-corticosterone is converted to corticosterone by 11B-hydroxylase.
- Step 3.1d: Corticosterone is converted to aldosterone of the mineralocorticoid group by Aldosterone synthase.
Step 2b: Pregnenolone is converted to 17a-hydroxypregnenolone by 17a-hydroxylase. There are two pathways 17a–hydroxypregnenolone can proceed.
- Step 3.2a: 17a-hydroxypregnenolone is converted to 17a-hydroxyprogesterone by 3B-HSD.
- Step 3.2b: 17a-hydroxyprogesterone is converted to 11-deoxycortisol by 21-hydroxylase.
- Step 3.2c: 11-deoxycortisol is converted to glucocorticoid by 11B-hydroxylase.
Step 3.3a: 17a-hydroxypregnenolone is converted to dehydroepiandrosterone of the androgens group by 17,20 lyase. Dehydroepiandrosterone can go down two pathways.
- Step 4.1a: Dehydroepiandrosterone is converted to androstenedione by 3B-HSD
- Androstenedione can be converted to testosterone by 17B-HSD.
- Step 4.1b: Androstenedione can be converted to estrone by aromatase.
- Step 4.1c: Estrone can be converted to 16a-hydroxyestrone by 16a-hydroxylase
Step 4.2: Dehydroepiandrosterone is converted to androstenediol by 17B-HSD.
Step 5: Androstenediol can be converted to testosterone by 3B-HSD. There are two pathways testosterone can go down.
- Step 6.1: Testosterone can be converted to dihydrotestosterone (DHT) by 5a-reductase.
Step 6.2: Testosterone can be converted to estradiol by aromatase.
Step 7: Estradiol is converted 16-a-hydroxyestradiol by 16a-hydroxylase.
Key enzymes: 17a-hydroxylase, 17-20 lyase, 5a-reductase, and aromatase
Enzyme pathways: The pathway starts in the hypothalamus, which sends a signal (LHRH) to the pituitary gland. The pituitary gland releases luteinizing hormone (LH) to the prostate, ovary, or adrenal gland. After which, testosterone or estradiol is produced.
Of note, women have aromatase in peripheral tissues as well.
Hormonal Agents
General Adverse Effects: fatigue, hot flashes, GI disturbances, decreased libido, edema, and metabolic changes (bone density, weight gain, dyslipidemia)
Testosterone ADRs: gynecomastia, hepatotoxicity
Estrogen ADRs: VTE risks and menstrual irregularity
Estramustine – “The Original Targeted Therapy”
Indication: Prostate cancer
This was where we started with hormonal therapy. The structure includes a nitrogen mustard moiety, and we discussed in the previous discussion, nitrogen mustard is an alkylating agent. Estramustine also has impacts on microtubules.
The agent works to bind selectively to estrogen receptors and deliver cytotoxic molecules to the cell.
Must be taken on an empty stomach.
Class ADRs: estrogenic side effects, impaired glucose tolerance, and severe myelosuppression (limit its use)
Androgenic Agents
Antiandrogens – “Potential for Ligand-Independent Activation”
Agents: Bicalutamide, flutamide, and nilutamide
Indication: Prostate cancer
These agents are direct androgen receptor antagonists. They are also reversible, which means that the body can find ways to get around this blockage because reversible inhibitors don’t have the greatest affinity. The body can get around this through DNA-based, alterations, receptor alternations, ligand-independent activation, and alternate pathways.
Due to this adjustment, antiandrogens are often used in combination with other agents. For example, bicalutamide is often used with LHRH.
Class ADRs: Refer to testosterone ADRs and general ADRs
Androgen Synthesis Inhibitor – “Mineralocorticoid Storm & Rich Man’s Ketoconazole”
Agents: Abiraterone (two formulations – Zytiga and Yonsa)
Indication: Prostate cancer
These agents are inhibitors of 17a-hydroxylase and 17,20-lyase (CYP 17 inhibitors). The end result is the prevention of testosterone and DHT.
The idea for this mechanism came from ketoconazole, which is an anti-fungal agent. Ketoconazole is a strong CYP inhibitor including CYP17. It was actually used to treat prostate cancer 30 years ago.
The first formulation of abiraterone was Zytiga, which is highly lipid soluble. This formulation is highly affected by high-fat meals (increase AUC by 10x). It is recommended to take Zytiga on an empty stomach.
The second formulation of abiraterone was Yonsa. This formulation is less affected by foods.
Class ADRs: General ADRs + Testosterone ADRs + mineralocorticoid storm, deficiency in mineralocorticoids (hypokalemia, edema, arrhythmias).
A little note on mineralocorticoid storm. Since we knocked out 17a and 17,20 lyase, the body cannot proceed with androgen production. The body recognizes that we have a deficiency of androgen and try to compensate. It comes up with an alternate pathway that pushes the reaction toward mineralocorticoid, resulting in mineralocorticoid storm. This explains the initial surge of mineralocorticoids, which triggers the negative feedback loop, and the body stops making aldosterone. This can lead to very severe consequences. Patients should be supplemented with 5-7.5 mg of steroids during the therapy.
Androgen Signaling Inhibitor – “Rare Edema”
Agents: Enzalutamide, apalutamide, and darolutamide
Indication: Prostate cancer
These agents have multiple mechanisms of action including inhibiting the translocation of androgen receptors, DNA binding, and activating coactivator recruitment.
They also act as anti-androgens with higher affinity than other anti-androgen agents.
Unlike abiraterone, these agents do not have food issues or mineralocorticoid storms since they do not inhibit the synthesis of testosterone.
Class ADRs: General ADRs + Testosterone ADRs + rare edema. Prednisone can be given for symptoms of negative feedback (due to an increase in overall synthesis), but this is not the standard.
Progestational Agents – “The Only Progestational Agent”
Agent: Megestrol acetate
Indications: breast cancer (decrease circulating estrogen) and endometrial (decrease endometrial hyperplasia)
Megestrol acetate works by acting as an anti-luteinizing agent in the pituitary. The indirect feedback can disrupt the estrogen cycle.
ADRs: General ADRs + Estrogen ADRs.
Estrogenic Agents
Selective Estrogen-Receptor Down Regulator – “Post-menopausal ER (+)”
Agent: Fulvestrant
Indication: ER (+) Post-menopausal breast cancer
Fulvestrant acts by binding to the estrogen receptor with high affinity and alters the receptor structure that limits the downstream pathway. In this way, it also acts as an anti-estrogen agent.
The goal of fulvestrant is to reduce the number of viable estrogen receptors over time.
Class ADRs: General ADRs + estrogen ADRs + injection reaction (very thick and viscous injections (2) given IM in the gluteal muscles monthly)
Aromatase Inhibitors – “Post-Menopausal”
Agents: Anastrazole, exemestane, and letrozole
Indication: breast cancer in post-menopausal patients
These agents competitively bind to inhibit the action of aromatase in only the peripheral tissues, where about 10% of estrogen is produced in pre-menopausal women. Aromatase is the key to estrogen production in post-menopausal women. This is why these agents are only used in post-menopausal women because otherwise there is no benefit since we’re blocking the other 90% estrogen production.
Anastrazole and letrozole have non-steroidal structures and are reversible. Exemestane has steroidal structure and is irreversible.
Class ADRs: general ADRs + estrogen ADRs + arthralgia and myalgias
Selective Estrogen Receptor Modulators (SERMs) – “Retinal Toxicity”
Agents: Tamoxifen and toremifene
Indications: breast, ovarian, and endometrial in both pre- and post-menopausal women
These agents inhibit the binding of estrogen receptors and block estrogen stimulation in breast cancer cells. Their actions are depended on the type of target issue either pro-estrogenic effect or anti-estrogenic effect.
Class ADRs: general ADR + estrogen ADR + retinal toxicity
These agents increase the risk of uterine cancer by increasing the proliferation in the uterine tissue. They reduce the risk of breast cancer. They can strengthen the bone. They are good on lipid profile but promote clotting factor production. (Overall, lower the risk of heart disease).
Tamoxifen is convereted to endoxifen in the body. It is 1000x more potent than tamoxifen. The effects can be blocked by SSRIs, which is why patients should be put on alternate antidepressants, such as NDRI.
Luteinizing Hormone-Releasing Hormone (LH-RH) Agonists – “Pre-menopausal”
Agents: Goserelin, Leuprolide, Triptorelin
The theory behind these agents is to overload the system and trigger the negative feedback loop.
- The initial surge of testosterone and estradiol, in the beginning, is expected. This can worsen the symptoms in the beginning. Direct hormone blockers may need to be used in the beginning.
- Continual exposure leads to a down-regulation and uncoupling of signal transduction as the body compensates for the overload.
- The body removes the receptors to compensate.
This process is reversible, and eventually, the system will reset back to normal after stopping the therapy.
Because this pathway works through the primary estrogen pathway where 90% of estrogen is produced, these agents can also be used in pre-menopausal women and not in post-menopausal because this pathway has already shut down.
Class ADRs: general ADRs, gynecomastia in men, and injection site reaction.
Leuprolide acetate (Lupron) is a nonapeptide in microspheres (help with long-acting) and must be diluted prior to use. It is injected IM in the thigh or gluteal muscles. Its dosing is a function of duration.
- Monthly dose: 7.5 mg
- Every 3 months: 7.5 mg * 3 = 22.5 mg
- Every 6 months: 7.5 mg * 6 = 45 mg
Goserelin (Zoladex) is a decapeptide in a copolymer implant. It is an SQ injection to the abdominal wall. The polymer is biodegradable and slowly releases the medication over time. Lidocaine can be used in combination to help with the injection pain.
- Monthly: 3.6 mg
- Every 3 months: 3.6 * 3 = 10.8
Luteinizing Hormone-Releasing Hormone Antagonists – “Prostate Only & No Flare”
Agents: Degarelix and relugolix
Indications: Prostate cancer
These agents target and block GnRH (both LH and FSH) receptors in the anterior pituitary. Because they are antagonists, we do not expect the initial flare that we would expect with LHRH agonists. They are monthly SQ injections.
Class ADRs: similar to LHRH agonists.