A Twenty-First Century Cancer Epidemic Caused by Obesity: The Involvement of Insulin, Diabetes, and Insulin-Like Growth Factors
Figure 4
Steroid hormone biosynthesis and therapeutic prevention of steroid hormone action. The sterol cholesterol which contains 27 carbons and includes four interconnected cyclic hydrocarbons is the precursor of all steroid hormones (a). Removal of the cholesterol side chain yields the 21-carbon pregnenolone which is metabolised further to give active progestogens which are in turn converted into glucocorticoids and mineralocorticoids (not shown). Pregnenolone and progesterone may be converted also to 17α-hydroxy pregnenolone and 17α-hydroxy progesterone which are the precursors of the 19-carbon androgens. Metabolism of androgens by aromatisation of the first cyclic hydrocarbon and removal of carbon 19 produces the 18-carbon oestrogens. Two important enzymes in the end stages of androgen and oestrogen synthesis are expressed in adipocytes: 17β-hydrosteroid dehydrogenase converts androstenedione into the much more potent testosterone and oestrone into the more potent oestradiol. Aromatase converts the androgens androstenedione and testosterone into oestrone and oestradiol, respectively. All steroid hormones interact with and activate a cognate receptor which is a ligand-dependent transcription factor. For instance, all active androgens interact with the androgen receptor and all oestrogens interact with an oestrogen receptor. Systemic therapeutic intervention to inhibit androgen or oestrogen action involves inhibition of enzymes involved in their synthesis (b) or competitive inhibition of the interaction of the steroid ligands with their receptors (c). Recently, 17α-hydroxylase inhibitors such as abiraterone and orteronel have been developed and are in clinical trial for the treatment of antiandrogen refractory prostate cancer. Inhibitors of 5α reductase such as finasteride and dutasteride are used in the treatment of benign prostatic hyperplasia and male pattern baldness. Aromatase inhibitors such as type I inhibitor anastrozole and type II steroid inhibitor exemestane are used widely in the treatment of postmenopausal women with breast cancer. Oestrogen antagonists include the partial antagonist tamoxifen which is a triphenylethylene derivative and the pure antioestrogen fulvestrant which is a steroid. Androgen antagonists include the nonsteroidal pure antiandrogens flutamide and bicalutamide which is the mainstay of systemic therapy in prostate cancer patients.
