Exercise and metabolic disease/prostate/Pathophysiology

Anatomy Background
The prostate is a group of exocrine glands of the male reproductive system that produce, store and secrete seminal fluid. This alkaline fluid assists spermatozoa longevity post ejaculation. The prostate itself surrounds a section of the urethra and is adjacent to the urinary bladder, seminal vesicle and rectum. The function of the prostate is regulated by androgens (male sex hormones).The androgen testosterone forms dihydrotestosterone once in the prostate, which is the major regulatory hormone of the prostate itself. [12]

Adenocarcinoma Background
Prostate cancer is an adenocarcinoma or glandular tumour formed by the uncontrolled and unregulated cell division and growth of prostate cells.[12] This tumour may grow overtime obstructing ejaculation and urination.[12] Once large enough the tumour may metastasise to surrounding tissues such as the bladder, seminal vesicle and rectum or travel to more distant areas of the body such as bones and lymph nodes via invading the blood stream and/or lymphatic ducts.[1]

An animated video of the pathophysiology of prostate cancer is available through http://www.youtube.com/watch?v=zg3j5Ig4dJY&feature=related

Androgen Deprevation Therapy
Androgen Deprivation Therapy (ADT) is effective in slowing many prostate cancers. There are many forms of ADT which all aim to decrease systemic levels of androgens upon which cancer cells growth is dependent on. ADT aims to decrease testosterone levels to <0.7-1.7nmol/L in order to stunt cancer growth as much as possible.

ADT Methods
Orchiectomy or castration involves completely removing the testosterone producing testes in order to lower serum levels of testosterone and inhibit prostate cancer growth. Medical or chemical castrations pharmacology such as gonadotropin-releasing hormone agonists (GnRH-As) and gonadotropin-releasing hormone antagonists reduces the production of lutenizing hormone through decreased pituitary receptors, leading to castration levels of testosterone. Orchiectomy removes the testes which does not inhibit the production of testosterone from the adrenal glands. Many androgen receptor antagonists may therefore be used in combination to ensure as low serum testosterone as possible via blocking the adrenal production of testosterone. Currently there are many androgen receptor inhibitors available including flutamide, bicalutamide, and nilutamide.

ADT side effects
As androgens play an essential role in sexual function, psychological health, bone mineral regulation and skeletal muscle (body composition) maintenance ADT also has many negative side effects.


 * Erectile dysfunction

Low testosterone is directly related to poor libido and erectile dysfunction in men. Two of the major chemicals involved in the process of an erection are nitric oxide and cyclic guanosine monophosphate. These are regulated by dihydrotestosterone, the major androgen that ADT aims to decrease, potentially causing erectile dysfunction.


 * Bone mineral density and skeletal muscle mass

Leutenizing hormone is responsible for the production of testosterone and estrogen. Estrogen plays a large role in bone remodelling and therefore bone mineral density. Estrogen stimulates the production of osteoclasts which lay down further bone matrix, while also inhibiting osteoclast production which cause the break down these bone mineral deposits. Therefore a decrease in testosterone and estrogen levels through ADT may cause a loss of BMD.

Muscle atrophy can be directly related to low testosterone levels. Testosterone is an anabolic androgen meaning it causes the building or growth of tissue, including protein synthesis and cellular hypertrophy in skeletal muscle. Catabolism of this tissue gradually occurs overtime as protein is used in low quantities as a fuel source. Testosterone also inhibits this catabolism of muscle tissue, allowing greater net protein synthesis and muscle growth. This catabolic effect is not as well balanced by the anabolic and inhibitory effect of testosterone when the body has very low testosterone levels. This demonstrates how the lack of testosterone caused by ADT can potentially lead to decreased muscle mass and therefore strength and muscular endurance. [2]


 * Anaemia

Testosterone is involved in the stimulation of erthropoiesis or the production of red blood cells. Therefore low serum levels of testosterone may cause a decline in red blood cell production, red blood cell concentration in the blood and therefore anaemia in ADT patients. Anaemia in many sufferers causes lethargy as the body’s ability to carry oxygen to working cells for energy is reduced. This may explain why any ADT patients report increased a fatigue during activities of daily living.