Treatment Indications and Pre-treatment

Treatment Modalities

Evaluations

Current available testosterone preparations

Testosterone replacement therapy is indicated

and delivery forms are reported in Table 17.4.

in patients with morning serum total testos-

Neither injectable preparations nor slow-

terone levels of <250 ng/dL and signs and

release pellets can reproduce the circadian

symptoms of androgen deficiency (Fig. 17.3).62

pattern of testosterone production of the tes-

In patients with borderline testosterone levels

tes. This is accomplished best by the trans-

and symptoms suggestive of androgen defi-

dermal preparations. Oral testosterone may

ciency, a short trial of testosterone replace-

also approximate a circadian rhythm by dose

ment may be justified.23 Testosterone admi-

adjustments even if the relevance of repro-

nistration is absolutely contra-indicated in

ducing a circadian rhythm during testoster-

men suspected of, or having, carcinoma of the

one therapy remains unknown. The choice of

prostate or breast. Relative contra-indications

appropriate testosterone delivery should be

include: significant polycythemia (hemat-

based on safety and efficacy while also taking

ocrit ³55%), untreated sleep apnea, severe ges-

into consideration factors such as cost and

tive heart failure, severe symptoms of lower

convenience. Selection will of course also

urinary tract obstruction evidenced by high

depend on the patient’s preference and that

scores on the International Prostate Symptom

of his physicians.63

Score or clinical findings of bladder outflow

obstruction (increased postmicturition resid-

ual volume, decreased peak urinary flow, path-

ological pressure flow-studies) due to an

Oral Preparations

enlarged, clinically benign prostate. Moderate

obstruction represents a partial contraindica-

Oral androgen preparations have

become

tion. After successful treatment of the obstruc-

popular because of their convenience aspects

tion, the contraindication

is lifted.23 A

such as dose flexibility, possibility of immedi-

prerequisite test before initiating testosterone

ate discontinuation and self-administration.

supplementation should include the prostate-

However, they demand special consideration

specific antigen (PSA) and

a

digital

rectal

because they undergo rapid hepatic and intes-

examination

(DRE) in men

older

than

tinal metabolism. An oral preparation that is

45 years.

widely used throughout the world is testos-

terone undecanoate. This product is designed

to deliver testosterone to the systemic circ-

ulation via the intestinal lymphatic route,

thereby circumventing first-pass inactivation

Free or bioavailable

in the liver. Therefore, it is free of liver toxic-

Testosterone

ity and brings serum testosterone levels

YES

within the physiological range.8 One of the

newest

testosterone

replacement

therapy

Normal

Low

modalities is transbuccal testosterone. Since

Symptoms and

buccal

testosterone is

transported

directly

signs

>350 ng/dL

<250 ng/dL

into the superior vena cava from the buccal

>12 nmol

<8,7 nmol

venous system, it avoids the first-pass effect

of hepatic metabolism. Levels peak

within

NO

30 min. attain a steady state within 24 h and

No

Testosterone

then drop below normal 2–4 h after the tablet

Testosterone

treatment

is removed. Transbuccal administration main-

treatment

tains testosterone at levels within the physio-

Figure 17.3. diagnostic flow-chart of patients suitable for

logical range, comparable to testosterone

testosterone replacement therapy.

gel.64

is higher than 4 ng/mL or abnormal DRE. When

metastatic prostate cancer.71 Although very clear

hematocrit is elevated during the therapy, dosage

evidence indicates that a reduction in serum tes-

reduction or cessation of treatment should be

tosterone due to castration concentrations is

considered according to severity. Potential Risks

able to reduce levels of prostate-specific antigen

Associated with Testosterone-Replacement The-

(PSA) and delay the progression of established

rapy are reported in Table 17.2.

prostate cancer, it is difficult to prove the con-

verse. Since 1941, a clear relationship between

Testosterone Replacement Therapy

circulating testosterone levels and prostate can-

cer has not been identified and still remains the

and Prostate Safety

subject of intense research study and debate.71

Clinical studies and basic investigations have

The prostate is an androgen dependent organ,

shown that the development and growth of pros-

with a high concentration of testosterone recep-

tate cancer are much more complex than simply

tors and a high 5-alpha reductase activity. As

an excess or lack of androgens. Testosterone reg-

growing numbers of aging males receive testos-

ulates prostate growth by modulating the bal-

terone substitution for management of the signs

ance between proliferative and apoptotic

and symptoms of hypogonadism, there has been

processes. The direct effect of testosterone on

a renewed interest in the role of testosterone in

prostate epithelial cells induces differentiation,

prostate health, particularly with regards to the

whereas the indirect effects on proliferation is

safety profile in terms of BPH and prostate

mediated by the growth factor production by the

cancer.

prostate stroma.72 Moreover, nonsteroidal hor-

mones (insulin, leptin, glucocorticoids, growth

hormone), genetic susceptibility, inflammation

Testosterone Replacement Therapy

and environmental factors appear to be signifi-

and BPH Progression

cant contributors to prostate growth. Recent evi-

Clinical studies have failed to demonstrate exac-

dence demonstrates the absence of a direct

correlation between serum and prostate andro-

erbation of voiding symptoms attributable to

gen levels. Marks et al. conducted a randomized,

benign prostatic hyperplasia during testosterone

double-blind study on 44 healthy men with

replacement therapy, and complications such as

serum testosterone levels of <300 ng/dL and

urinary retention have not occurred at higher

related symptoms in order to investigate the

rates than in controls receiving placebo. Prostate

effects of testosterone replacement therapy on

volume, as determined by ultrasonography,

prostate tissue.Patients were treated with 150 mg

increases significantly during testosterone-

testosterone enanthate or placebo intramuscu-

replacement therapy, mainly during the first 6

larly every 2 weeks for 6 months. Prostate biop-

months, to a level equivalent to that of men with-

sies were available before and after treatment in

out hypogonadism. However, urine flow rates,

40 men. Testosterone therapy resulted in a sig-

postvoiding residual urine volumes, and prostate

nificant increase in testosterone and dihydrotes-

voiding symptoms do not change significantly in

tosterone (DHT) levels in the serum, but not in

patients receiving testosterone replacement

prostate tissue. Total PSA levels were signifi-

therapy. This apparent paradox is explained by

cantly increased by both testosterone (from 1.55

the poor correlation between prostate volume

to 2.29 ng/mL) and placebo (from 0.97 to 1.10 ng/

and urinary symptoms.69,70

mL) but still remained relatively low. Four new

cases of prostate cancer were diagnosed in the

Testosterone Replacement Therapy

placebo group and two new cases in the testos-

and Prostate Cancer

terone replacement group. Testosterone replace-

ment therapy also had no effect on prostate

The theory that testosterone may stimulate the

histology, tissue biomarkers for cell prolifera-

growth of prostate cancer derives from the orig-

tion, androgen receptors, or angiogenesis nor on

inal studies conducted by Huggins and Hodges

the expression of known androgen-regulated

in 1941, where the authors demonstrated that

genes or those related to cell stress or angiogen-

the marked reductions in serum testosterone

esis.73 Apparently, the internal environment of

following castration resulted in a regression of

the prostate is buffered against wide fluctuations