with advanced prostate cancer by demonstrat-

cortex. At the bone marrow level it acts as a

ing a statistically significant decline in cognitive

hematopoietic growth factor by regulating the

tests evaluating verbal memory and executive

feedback control of red cell production thereby

functions after 6 months.87 In a further study by

adapting the red cell mass volume to the level of

Jenkins et al., a significant cognitive decline in

the oxygen tissue required to satisfy tissue oxy-

spatial memory and spatial ability was demon-

gen demands.94,95 EPO production is primarily

strated in men with localized prostate cancer

regulated by hypoxia which acts at the gene

who received ADT.88 On the contrary, however,

transcription level by increasing gene expres-

other studies demonstrated no detrimental

sion. At the bone marrow level, EPO regulates

effects on cognitive functions brought on by

erythroid cell proliferation, differentiation, and

ADT.89

survival by binding to an EPO receptor which is

expressed primarily on the erythroid cells

Bone Metabolism

between the colony forming unit-erythroid

(CFU-E) and the pronormoblast stage of eryth-

Studies demonstrate that ADT may result in a

roid cell development. The number of EPO

significant decline in bone mineral density

receptors per cell gradually decreases during

(BMD) at multiple sites due to increased bone

erythroid cell differentiation and studies have

turnover resulting in a higher risk of developing

shown that the reticulocyte and mature eryth-

osteoporosis.82,90 During initial ADT, the BMD

rocyte do not contain EPO receptors.96-98 In nor-

of the hip and spine decrease by approximately

mal human subjects, serum levels of EPO range

3% per year. Later, BMD continues to decline

between 1 and 27 mu/mL.99 A variety of mecha-

steadily during the course of long-term therapy.

nisms for EPO down regulation have been

The risk of developing osteoporosis during ADT

reported: hyperoxia, increased catabolism by an

depends on individual differences in peak bone

expanded erythroid progenitor cell pool, blood

mass and the amount of adult bone loss occur-

hyperviscosity, renal disease and cytokine pro-

ring before ADT. Individual variations in bone

duction during inflammatory, infectious and

loss rates during ADT have been reported. The

neoplastic disorders.100 The mechanism for the

decline of BMD due to both medical or surgical

anemia of chronic renal failure is probably due

castration leads to a statistically significant and

to the inability of the kidneys with compromised

clinically meaningful increase in fracture risk

renal function to produce sufficient amounts of

within 5 years of commencing therapy.89 In large

EPO to meet the demands for new red cell pro-

population-based studies, ADT was associated

duction. Nevertheless, the uremic state may also

with an approximate 21–45% relative increase

blunt the bone marrow response to EPO.101,102

in the incidence of clinical fractures.91-93 Longer

treatment duration seems to confer greater frac-

Calcitriol

ture risk.

Calcitriol (Vitamin D3 or 1,25 dihydroxychole-

calciferol) is a steroid hormone with a wide range

The Kidneys

of biological effects. It has long been known for

its role in regulating serum levels of calcium and

Endocrine Functions of the Kidney

phosphorus, and bone mineralization. More

recently, it has been demonstrated that receptors

Beyond excretory function, the kidneys act as

for vitamin D are present in a wide variety of

cells, and that calcitriol generates multiple bio-

complex endocrine organs. The main hormones

logical responses via both genomic and nonge-

secreted by the kidneys are: erythropoietin

nomic pathways. Immune and cardiovascular

(EPO), the active form of Vitamin D (1,25-dihy-

systems have been identified as critical targets

droxycholecalciferol) and renin.

for calcitriol actions.103 Calcitriol is synthesized

through complex biosynthetic pathways involv-

Erythropoietin

ing the skin, the liver and the kidneys in a step-

wise manner. The final biosynthetic step consists

EPO is a 34-kDa glycoprotein hormone mostly

of the hydroxylation of the major circulating

synthesized by interstitial cells of the kidney

metabolite, 25-hydroxyvitamin D3, performed