24.03.6 Steroid Hormones and their Antagonists

The growth of a number of tumours have been demonstrated, in part, to be positively or negatively regulated by the presence of various steroid hormones. This has afforded the opportunity to develop treatments specifically targeted to these cancers. For example, many breast cancers depend on proliferative signals produced by oestrogens to support their growth. Indeed, oestrogen receptors are over-expressed in some 70% of all breast cancers making these tissues especially sensitive to the action of the steroids (oestrogen receptor positive breast cancer). Treatment involves either the use of agents to inhibit the pathways of endogenous oestrogen synthesis (aromatase inhibitors) or SERMs (selective oestrogen receptor modulators) that subvert the actions of the steroid. The aromatases are a group of enzymes involved in the synthesis of steroids from precursor cholesterol. Principal amongst these reactions is the first stage conversion of cholesterol to pregnenolone which inturn gets converted to mineralocorticoids, glucocorticoids, androgens as well as oestrogens. The aromatase inhibitors (anastrazole, exemestane, letrozole) block this first step reducing the oestrogen biosynthesis and removing proliferative signals to the hormone-sensitive cancer tissues. Normal chemotherapeutic adverse effects are seen with these compounds though rare instances of thrombosis have been noted with administration of letrozole. SERMs are drugs that act specifically on oestrogen receptors where they can behave as agonists or antagonists depending on the tissue targeted. Tamoxifen is a SERM indicated for use in oestrogen receptor positive breast cancers where it acts as antagonists to the breast tissue oestrogen receptors blocking activation of oestrogen-responsive genes stopping RNA synthesis. The result is a depletion of oestrogen receptors and suppression of the steroid’s proliferative effects. Adverse effects include hot flushes, nausea, vomiting, skin, rash and vaginal bleeding and discharge. However, tamoxifen acts as oestrogen receptor agonists is other tissues including bone, thereby avoiding the increased risk of osteoporosis that accompanies the removal of endogenous oestrogen.

Progression of prostate cancer is under sophisticated hormonal control. Gonadotropin releasing hormone (GnRH) is secreted by the hypothalamus and interacts with specific receptors on the anterior pituitary gland which in turn facilitates the release of the gonadotropic hormones, follicle stimulating hormone (FSH) and luteinising hormone (LH) which are responsible for the secretion of testosterone and oestrogen. Exposure of the prostate to testosterone is implicit for the growth and survival of certain prostate cancers and so blocking the production or action of this hormone presents an important opportunity for therapy. Leuprolide and goserelin are analogues of GnRH and act as agonists at the GnRH receptor on the anterior pituitary gland. Chronic activation of these receptors by these drugs results in downregulation of the receptors and consequent inhibition of gonadotropin release resulting in a decrease in tumour growth and survival. These drugs also have some benefit in the treatment of advanced breast cancer. Adverse effects include impotence and hot flushes.

Synthetic, non-steroidal, antiandrogens (flutamide, bicalutamide) are also used in the treatment of prostate cancer. These drugs bind to androgen receptors (particularly testosterone receptors) on the prostate, competing with the endogenous steroid, impairing tumour growth. Adverse effects include gynecomastia (abnormal development of mal breast tissue) and gastrointestinal problems. Liver failure has been noted in rare cases with flutamide.

Prednisone is a potent, synthetic glucocorticoid that inhibits cell division by interfering with DNA synthesis. It is widely used in the treatment of acute lymphocytic leukaemia and Hodgkin and non-Hodgkin lymphoma. Adverse reactions are those primarily associated with glucocorticoid treatmentweight gain, ulcers, pancreatitis, cataract and glaucoma formation, osteoporosis and mood change (euphoria, psychosis).