Hormone Therapy

"Hormone-related cancers, namely breast, endometrium, ovary, prostate, testis, thyroid and osteosarcoma, share a unique mechanism of carcinogenesis. Endogenous and exogenous hormones drive cell proliferation, and thus the opportunity for the accumulation of random genetic errors."•

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Hormone substances are of two general types:

• Water-soluble hormones are amines and proteins that do not passively diffuse through the cell membrane. Instead, water soluble hormones bind to their respective receptors expressed on the extracellular surface of the target cell membrane. When a water soluble hormone binds to its extracellular membrane receptor an intracellular signalling pathway is activated. Activation of such an internal signalling pathway results in the up-regulation or inhibition an associated cellular process. In a cancer cell, activation may lead to: a) Increased cell proliferation, b) Decreased apoptosis, c) Enhanced motility, d) Angiogenesis.
  
• Lipid-soluble hormones easily diffuse through the cell membrane. Steroid hormones are the most common circulating lipid-soluble hormones. Steroid hormones include: testosterone, estrogens, progesterone, aldosterone and cortisol. The majority of steroid molecules circulate in the blood bound to a globulin carrier molecule. Free steroid molecules passively diffuse through a cell's lipid membrane. Inside the cell the steroid hormone binds to a specific intracellular receptor, forming a hormone/receptor complex (HRC). The HRC is transported into the nucleus of the cell where it activates the transcription of specific genes on the DNA molecule. Transcription of a gene produces messenger RNA that is transported out of the nucleus to be translated into a protein in the cytosol. The synthesized protein then influences a particular cellular activity. The pathologic response in cancer cells may include: a) increased cell proliferation, b) decreased apoptosis, c) enhanced motility, d) angiogenesis.
  

Hormones and antagonists

These agents are used to treat hormone-sensitive tumors. Hormone-sensitive tumors may be hormone-dependent, hormone responsive, or both. A hormone-dependent tumor regresses on removal of the hormonal stimulus. Hormone-responsive tumors regress when pharmacologic amounts of hormones are administered.

• Glucocorticoids are steroid hormones that include: prednisone, prednisolone, methlyprednisolone, dexamethasone, and hydrocortisone, etc. "Glucocorticoids are a mainstay of therapy for many lymphomas and leukemias, due to the ability of such steroids to prevent the growth and to cause the apoptotic death of these malignant cells."• They are also used in supportive care to reduce nausea, and suppress the acute toxic effects chemotherapy on healthy tissue.

• Class I nuclear receptor (NR) mechanism of action. Hormone binding to the NR triggers dissociation of heat shock proteins (HSP), dimerization, and translocation to the nucleus, where the NR binds to a specific sequence of DNA known as a hormone response element (HRE). The nuclear receptor DNA complex in turn recruits other proteins that are responsible for transcription of downstream DNA into mRNA, which is eventually translated into protein, which results in a change in cell function.

  Estrogens are steroid hormones necessary for normal human development, procreation and homeostasis. Both women and men utilize the enzyme aromatase to convert the androgens to estrogens. The ovaries are the primary site of estrogen synthesis in pre-menopausal women. Post-menopausal women synthesize estrogen from adrenal androgens using aromatase in the breast, skin, brain, adipose, muscle, and bone. Males utilize aromatase primarily in Leydig cells, Sertoli cells, spermatocytes, bone and adipose tissues.
  
  Estrogen regulates cell proliferation and differentiation in the target cell through hormone receptor complex (HRC) mediated gene transcription. Estrogen binds with an estrogen receptor in the cytosol, forming an hormone receptor complex. The HRC binds to an hormone response element (HRE) on DNA and activates genes responsible for cell division, inhibition of cell death, new blood vessel formation and protease activity. Estrogen has two class I nuclear receptors, ERalpha and ERbeta. These two receptors have different distribution ratios depending on the type of tissue and cancer status. ERalpha appears to regulate the cancer promoting effects of estrogen in ERalpha-positive breast carcinoma and is the target of the drug tamoxifen. ER-beta appears to have anti-proliferative and cell differentiation effects and is being investigated as a treatment target.•  
  
  

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  • Estrogen Synthesis Inhibitors: aromatase inhibitors and gonadotropin-releasing hormone deny estrogen dependent cells the hormone required to grow and proliferate.
    • Aromatase inhibitors cannot inhibit all of the estrogen producing capacity of the aromatase enzyme located in the ovaries and are therefore prescribed for post-menopausal or oopherectomized women.
      • Letrozole binds to the aromatase enyme which inhibits the conversion of androgens to estrogens.
      • Anastrozole binds to the aromatase enyme which inhibits the conversion of androgens to estrogens.
      • Exemestane binds irreversibly to the active site of aromatase causing its inactivation.
      • Aminoglutethimide inhibits aromatase conversion of androgens at low dose and blocks conversion of cholesterol at high dosage.
    • Gonadotropin-Releasing Hormone Agonists (GnRH) work by "downregulating pituitary GnRH receptors, thereby suppressing the release of luteinising hormone (LH) and follicle stimulating hormone (FSH), which, in turn, reduce the main source of oestradiol production in the ovaries."•  In males LH is responsible for testosterone production.
  • Selective Estrogen Receptor Modulators (SERM) - tamoxifen, raloxifene and toremifene all competitively bind to estrogen receptors.
    • Tamoxifen competes with estrogen to bind with estrogen receptors ER-alpha. Binding alters receptor conformation and estrogen dependent gene expression. Tamoxifen produces antiestrogenic effects in responsive breast tissue and estrogenic effects in bone.
    • Raloxifene, similar to tamoxifen, produces antiestrogenic effects in responsive breast tissue and estrogenic effects on bone, presumably by inhibiting the proliferation of preosteoclastic cells.
    • Toremifene, similar to tamoxifen, competes with estrogen for receptor binding sites. It producie antiestrogenic effects in responsive tumor cells by inhibiting expression of the estrogen dependent growth-stimulating genes. Inhibiting growth stimulation may promote apoptosis.
  • Selective Estrogen Receptor Down-Regulators (SERDs) - fulvestrant is an estrogen antagonist in bone, breast and uterus. It competes with estrogen for the binding site on the estrogen receptor and then degrades and eliminates the receptor before it can bind to DNA. Fulvestrant can lead to apoptosis in estrogen dependent cancer cells. SERDs are an important step forward because resistance to aromatase inhibitors and SERMs often occurs due to ERalpha positive breast cancer cell mutations that allow tumor recurrence in very low estrogen environments.•
    
    
• Androgens are steroid hormones necessary for the normal development, procreation and homeostasis in males and females. The ovaries synthesize androstenedione and convert it to testosterone and estradiol. Males synthesize androstenedione and convert it to testosterone in the testes. Testosterone is further converted to the more active molecule dihydrotestosterone DHT in skin, prostate and epididymis.
  
  Testosterone is essential to fetal development of male internal and external reproductive organs. In the adolescent and adult male, testosterone inhibits fat deposition, promotes skeletal muscle mass, is essential for the production of sperm and promotion of libido. Testosterone in the female serves primarily as a prohomone for the synthesis of estrogens and may promote libido. Like estrogens, androgens modifies target cell activitiy through hormone receptor complex (HRC) mediated gene transcription. Androgens have their own Class I Nuclear receptors and similar to estrogen the receptors must act as a dimer. Currently there are two known androgen receptors (AR), ARalpha and ARbeta.
  
  
  • Antiandrogen medications may be prescribed for a number of conditions or disorders including: prostate cancer, alopecia, acne, amenorrhea, hirsutism, polycystic ovary syndrome, gender reassignment, paraphilias, virilization.
    • Leuprolide is a synthetic non-peptide analogue of gonadotropin-releasing hormone. Leuprolide binds to and activates gonadotropin-releasing hormone (GnRH) receptors. Continuous, prolonged administration of leuprolide in males results in pituitary GnRH receptor desensitization and inhibition of pituitary secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH), leading to a significant decline in testosterone production; in females, prolonged administration results in a decrease in estradiol production. This agent reduces testosterone production to castration levels and may inhibit androgen receptor-positive tumor progression.
    • Goserelin is a synthetic analog of luteinizing hormone-releasing hormone (LHRH). Continuous, prolonged administration of goserelin in males results in inhibition of pituitary gonadotropin secretion, leading to a significant decline in testosterone production; in females, prolonged administration results in a decrease in estradiol production.
    • Triptorelin is a synthetic agonist analog of luteinizing hormone releasing hormone (LHRH). Possessing greater potency than endogenous LHRH, triptorelin reversibly represses gonadotropin secretion. After chronic, continuous administration, this agent effects sustained decreases in LH and FSH production and testicular and ovarian steroidogenesis. Serum testosterone concentrations may fall to levels typically observed in surgically castrated men.
    • Abarelix is a synthetic antagonist of naturally occurring gonadotropin-releasing hormone (GnRH). Abarelix directly and competitively binds to and blocks the gonadotropin releasing hormone receptor in the anterior pituitary gland, thereby inhibiting the secretion and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). In males, the inhibition of LH secretion prevents the release of testosterone. As a result, this may relieve symptoms associated with prostate hypertrophy or prostate cancer, since testosterone is required to sustain prostate growth.
    • Flutamide competitively block dihydrotestosterone binding at androgen receptors, forming inactive complexes which cannot translocate into the cell nucleus. Formation of inactive receptors inhibits androgen-dependent DNA and protein synthesis, resulting in tumor cell growth arrest or transient tumor regression.
    • Bicalutamide competitively binds to cytosolic androgen receptors in target tissues, thereby inhibiting the receptor binding of androgens. This agent does not bind to most mutated forms of androgen receptors.
    • Cyproterone binds the androgen receptor (AR), thereby preventing androgen-induced receptor activation in target tissues and inhibiting the growth of testosterone-sensitive tumor cells. This agent also exerts progestational agonist properties at the level of the pituitary that reduce luteinizing hormone (LH), resulting in reductions in testicular androgen secretion and serum testosterone levels. Treatment with cyproterone alone results in incomplete suppression of serum testosterone levels.
    • Finasteride competitively binds to and inhibits steroid type II 5-alpha-reductase in the prostate gland, liver, and skin, thereby interfering with the enzymatic conversion of testosterone to 5-dihydrotestosterone (DHT) and reducing serum DHT levels. The reduction in serum DHT levels results in diminished stimulation of androgen receptors in the nuclei of prostate cells and, so, diminished prostate cell proliferation. It has been demonstrated that regular use of finasteride for up to 7 years decreased the risk of low-grade prostate cancer in men age 55 and older.

• Growth Hormones are water-soluble hormones that promote cell growth. Defective hormonal signalling due to excess hormone production or abnormal receptor expression and activation can disrupt the normal cell proliferation and differentiation programs leading to malignant transformation. For example, epidermal growth factor receptor (EGFR) function is frequently deregulated in epithelial tumors, and EGFR signaling has been shown to play an important role both in cancer progression and in epithelial to mesenchymal transition.•  Another example involves the abnormal activation of insulin-like growth factor-1 receptor (IGF-IR) which induces mammary cells to undergo epithelial to mesenchymal transition that is associated with a dramatic increase in migration and invasion.•
  • Growth hormone inhibitors
    • Lanreotide is a somatostatin analog with a high affinity for human somatostatin receptors (SSTR) 2 and 5. Activity at human SSTR2 and 5 is the primary mechanism believed responsible for human growth hormone inhibition. Lanreotide is FDA "approved for the treatment of patients with unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival".•
      
      

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