Hormones and Prostate Cancer
Steve Parcell, ND
The hormonal hypothesis is one of the most important biologically plausible hypotheses in prostate cancer etiology. In addition to hormones, other possible causative factors include; dietary fat, calcium, dairy products and genetic polymorphisms. The purpose of this paper is to provide a background for the understanding of how various hormones may be implicated in this disease. Because of the difficulty in measuring hormones within the prostate itself and the lack of data on how tissue levels of hormones correlate with serum levels much of what we know on the relationship between hormones and prostate cancer is speculative . Epidemiological studies have used serum levels of androgens. Out of 12 prospective studies on the role of serum androgens in prostate cancer only one was able to show that men with higher serum levels of testosterone have a higher risk of prostate cancer .
Androgens are formed in the testes, adrenal glands, skin and prostate. Testosterone and dihydrotestosterone (DHT) are the two most important androgens in males. Testosterone predominates in the circulation whereas DHT predominates in tissue. About 44 percent of testosterone is bound to sex hormone binding globulin, 54 percent is bound albumin, and only 1-2 percent is free. The testes secrete only 25 percent of DHT whereas 65-75 percent is created by irreversible peripheral conversion (prostate and skin) through the action of 5-α reductase. Humans have two types of this enzyme. Type 1 is expressed motly in the skin and hair while type 2 is expressed androgen target tissue (prostate and genital skin) . Male pattern baldness and chest hair are associated with DHT metabolism in the skin and polymorphisms of androgen receptor, helping to explain racial/ethnic differences associated with male hormones . Within the prostate, DHT can undergo inactivation by five different enzymes. Conversion to3 β diol and 3α diol are the most important metabolites reflecting intracellular DHT concentration .
Within the prostate, DHT binds to androgen receptor with much greater affinity than testosterone. The DHT-receptor complex then binds to prostate DNA, where it activates the transcription of several androgen sensitive genes; this results in cellular proliferation and DNA synthesis.
Androgen receptor alone has been implicated in prostate cancer. It has been shown that in the absence of androgens non-androgen hormones can combine with this receptor, triggering androgenic action in cancer cells . It has also been demonstrated that mutations in the gene for the androgen receptor may result in mutant receptors with increased hypersensitivity to androgenic stimulation . In both situations, receptor activation can lead to promotion of tumor growth independent of androgens.
In addition to the androgen receptor, androgen receptor proteins (co activators) can also act as ligands thus increasing androgenic action within the prostate [7, 8].
Estrogens: Estrogen is used in the treatment of advanced prostate cancer; however, evidence suggests that estrogens, by binding to sex hormone binding globulin, participate in prostate growth and function . Estrogens may also help activate insulin–like growth factor synthesis (discussed below). In rats, prostate tumors are promoted by the administration of estradiol, suggesting that androgens and estrogens act together in the development of cancer . So how can estrogen possibly protect against tumor growth and promote tumor growth at the same time? At large dosages, estrogens may have anti-tumor effects by acting on the hypothalamic axis while at normal physiologic levels they may act as growth promoters . Current epidemiological data is too inconclusive to determine a positive or negative effect of estrogen in prostate cancer .
Sex hormone binding globulin (SHBG): SHBG is a carrier protein and regulator of free testosterone and estrogen, mediates steroid hormone signal transduction, and may activate the androgen receptor when bound to estradiol . Higher levels of SHBG are associated with lower levels of free testosterone and decreased prostate cancer risk .
Insulin and leptin are involved in the regulation of body fat distribution and lipid and glucose metabolism. Insulin may affect prostate cancer risk through the obesity hormone or insulin-like growth factor (IGF-I ) hormone pathways and can affect androgen biosythesis and metabolism. Insulin is a mitogen, may promote growth of prostatic epithelial cells, is anti-apoptotic, and can bind the and activate the IGF-I receptor . Insulin also increases levels of in insulin-like growth factor through its down regulation of insulin-like growth factor binding protein . Insulin-like growth factor has been implicated in the regulation of prostate epithelial cell proliferation and the etiology of prostate cancer .
One hypothetical scenario is the following :
1. Westernization: High fat and simple sugar diet and inactivity and genetic factors
2. Hyperinsulimemia or insulin resistance
a. ↑Androgen biosynthesis, ↑ androgen receptor, ↓ SHBG → ↑ androgenic action
b. ↑ in IGF system → ↑ IGF-I receptor
3. ↑ in prostate cancer
Leptin is the protein product of the obesity gene and may also be implicated due to its role in regulating fat distribution and sex hormones. Leptin increases adipose tissue, regulates food intake and energy balance as well as numerous other interactions within the endocrine system . Increased adipose (especially abdominal) is associated with hyperinsulinemia and insulin resistance. Insulin, in turn, increases leptin gene expression and production. The phenomenon of Westernization is associated with an increased risk of getting prostate cancer among migrates to the United States .
The interplay of hormones in humans is difficult to study because some have a short half life and because of the episodic nature of their secretion. Androgens, SHBG, estrogens, insulin, leptin, diet, lifestyle and obesity all have a potential role in the etiology of prostate cancer. It is also possible that these factors act synergistically to promote tumor growth. There also may be yet to be identified factors responsible for the association between Westernization and prostate cancer, (environmental toxins, type of dietary fat, electromagnetic radiation, in utero exposure to xestrogens etc.) and these deserve further research.
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