Testosterone – not just a replacement therapy

Most of us associate testosterone with

normal male development – the voice

deepens, the energy levels are sus-

tained, muscle mass and strength is

increased and sex drive is maintained.

In addition, testosterone causes the

growth of pubic and body hair

(though it can also lead to baldness)

and benefits bone strength, but can

also decrease high-density lipoprotein

(HDL) cholesterol. However, the

impact of a reduction in HDL choles-

terol only appears to affect HDL3c,

which is the least antiatherogenic sub-

fraction, and overall no atherogenic or

antiatherogenic effects have been

recorded (1).

There are, however, several reports

of a link between low testosterone

levels and coronary artery disease as

well as the more predictable reduc-

tion in libido, increased fatigue, mus-

cle weakness, osteoporosis, depression,

poor concentration and erectile dys-

function (ED) (2,3). In this issue,

Shabsigh et al. provide an overall

review of the role of testosterone in

the treatment of ED (4). In addition

to taking a thorough history clarify-

ing whether the problem is sex drive

(libido), ED or both (important

because men may equate ED with

sex drive in their minds when their

drive is normal), there is a recom-

mendation to screen all men with

ED from 50 years of age for hypogo-

nadism. Testosterone is at its highest

in the morning and samples should

be obtained before 10 AM. Shabsigh

et al. (4) emphasise the importance

of testosterone replacement therapy

with regard to treating ED usually in

combination with a phosphodiesterase

type 5 inhibitor (sildenafil, tadalafil,

vardenafil), especially in those at risk

for hypogonadism and ED, such as

type 2 diabetics, and those with mul-

tiple risk factors for vascular disease

which may be clustered as the meta-

bolic syndrome (1,4).

One of the problems with testoster-

one levels is the variability between

laboratories in the definition of the

normal range. However, if we accept a

range from 8–12 to 35–45 nmol/L

this still presents a problem because of

the width of the range. A level of

12 nmol/L may be perfectly normal

for most men but not adequate for

some, so there needs to be a clinical

and biochemical correlation. If a man

with ED and low normal testosterone

is not responding fully to a phospho-

diesterase type 5 inhibitor, he may

benefit from testosterone replacement

therapy in a similar manner to those

in Shabsigh et al.’s paper (4).

Hypogonadism in men over

50 years is often known as the ‘andro-

pause’ though technically the terms

are late onset hypogonadism (LOH)

or androgen decline in the ageing

male (ADAM). Treatment improves

physical and mental well-being, qual-

ity of life (including sex life), bone

density increases and there may be an

overall vascular benefit. Negatives

include aggravating existing prostate

cancer but not causing prostate cancer,

reducing sperm count so a check

needs to be made on family intentions

regarding children, and increasing

haematocrit (polycythaemic men need

careful monitoring).

In the review of testosterone ther-

apy in hypogonadism and the meta-

bolic syndrome, an argument was

made to not only treat the hypogona-

dism with testosterone, but also in

doing so, the metabolic syndrome’s

progression to overt diabetes or car-

diovascular disease could be slowed or

stopped (1). The link between a low

testosterone and aortic atherosclerosis

in men was found to be independent

of other risk factors but not in

women, and the authors raised the

tantalising question of using testoster-

one to protect against atherogenesis in

men (1).

When English et al. challenged the

concept that physiologically high levels

of androgens accounted for men’s

increased relative risk for coronary dis-

ease, reporting lower levels of andro-

gens when compared to men with

normal coronary arteries, they pointed

out the potential benefit of replace-

ment therapy on quality of life with

no increased cardiovascular risk and a

potential benefit (3). More recently

testosterone administration has been

shown to have anti-ischaemic potential

in men with angina and the LOH

with cardiovascular risks reversed by

testosterone replacement (5–7).

In men presenting with coronary

disease, measuring testosterone should

be part of the assessment, especially

if ED and/or diabetes coexist.

Replacement can only be advocated

if there are clear signs or symptoms

of androgen deficiency including ED,

but the long-term cardiovascular risk

reduction and symptom management

potential merits further study. Repla-

cing testosterone can lead to a life-

long benefit on quality of life but

the detection of a low testosterone

should also trigger a search for other

vascular risk factors whilst treatment

progresses.

Graham Jackson

Editor

R E F E RE N C E S

1 Makhsida N, Shah J, Yan G et al.

Hypogonadism and metabolic syn-

drome: implications for testosterone

therapy. J Urol 2005; 174: 827–34.

2 Hak AE, Witteman JCM, DeJong FH

et al. Low levels of endogenous andro-

gens increase the risk of atherosclerosis

in elderly men: The Rotterdam Study.

J Clin Endocrinol Metab 2002; 87:

3632–9.

3 English KM, Mandoor O, Steeds RP

et al. Men with coronary artery dis-

ease have lower levels of androgens

EDITORIAL d o i : 1 0 . 1 1 1 1 / j . 1 7 4 2 - 1 2 4 1 . 2 0 0 6 . 0 1 1 1 2 . x

ª 2006 The AuthorsJournal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, September 2006, 60, 9, 1021–1027

than men with normal coronary

angiograms. Eur Heart J 2000; 21:

890–4.

4 Shabsigh R, Rajfer J, Aversa A et al.

The evolving role of testosterone in the

treatment of erectile dysfunction. Int J

Clin Pract 2006; 60: 1087–92.

5 Rosano GC. Androgens and coronary

artery disease. A sex specific effect of

sex hormones? Eur Heart J 2000; 21:

868–71.

6 Isidori AM, Gianetta E, Greco EA

et al. Effects of testosterone on body

composition, serum lipid profile in

middle aged men: a meta-analysis. Clin

Endocrinol 2005; 63: 280–93.

7 Malkin CJ, Pugh PJ, Morris PD et al.

Testosterone replacement in hypogo-

nadal men with angina improves isch-

aemic threshold and quality of life.

Heart 2004; 90: 871–6.

Lipid lowering, statins and cancer

Why the interest in lipid-lowering

drugs and cancer? This is an old story

and dates back to jeremiads issued in

the early days of lipid-lowering drug

therapy. Analyses of epidemiological

studies showed that low levels of cho-

lesterol were associated with excess

cancer (1,2). The first intervention

studies with lipid-lowering drugs

showed significant benefits on cardio-

vascular events but the first large-scale

endpoint study – the World Health

Organization Clofibrate Study scared

everyone (3). This study showed a

20% reduction in cardiovascular

events at 5 years at the expense of a

20% increase in total mortality (4).

Later re-analysis of the data after fol-

low up for 8 years reduced the excess

mortality to 11% and identified many

of the excess events as due to the con-

sequences of cholecystectomy but

there was still a suggestion of excess

cancers (5). Similarly later fibrate

studies including the Helsinki Heart

Study also showed reductions in car-

diovascular events but no reduction in

total mortality and a non-significant

increase in cancers at 8.5 years (30 vs.

18; p ¼ 0.08) but this resolved by

10 years (6). In addition, fibrate ther-

apy in rats resulted in an increase in

colon carcinomas (7). Hence, the story

that lipid lowering causes cancer,

which has bedevilled the field of

atherosclerosis, arose over the last dec-

ade (8,9). Everyone forgot that associ-

ation and causality are not identical

(1,2). In actual fact, reverse causality

operates in this area – cancers cause

low cholesterol through induction of

cytokines (10). Despite this mechan-

ism, the sceptics have demanded fur-

ther evidence with each new class of

lipid lowering drug and each individ-

ual compound and lately each dose

(9).

Statins reduce cardiovascular events

and have been proven to reduce car-

diovascular mortality in secondary pre-

vention. Yet despite the publication of

the Scandinavian Simvastatin Survival

Study (4S) in 1995 that showed no

difference in cancers at 5 years (11) or

later 10 years (12), doubts persisted.

When the results of the Cholesterol

and Recurrent Events (CARE) Study

were presented in 1996 the story reap-

peared (13). There was a 12-fold

increase in breast cancer. Actually 12

cases vs. 1 case, many in patients with

pre-existing disease who had been

recruited into the trial in a study of

middle aged individuals (80% men)

totalling 20,000 patient years. In con-

trast, colorectal cancers were reduced

(12 cases vs. 21 cases) and overall

there was little difference in cancer

incidence (172 cases vs. 161 cases).

Emergency analyses were conducted of

the concurrent 9014 patient 5-year

Long-term Intervention with Pravasta-

tin in Ischaemic Heart Disease

(LIPID) study prior to its completion

and reassurance was gained from the

fact that combining the studies

pravastatin therapy was associated with

non-significant numbers of cancers

(22 cases vs. 11 cases) in a study

where pravastatin therapy was associ-

ated with reduced cancer incidence

(379 cases vs. 403 cases) (14). In the

PROspective Study of Pravastatin in

the Elderly at Risk (PROSPER) study

pravastatin therapy in 5804 individu-

als aged 170 years was associated

with an increase in cancer [115 cases

vs. 91 cases; RR ¼ 1.28 (0.97–1.68);

p ¼ 0.08] with the excess due to

gastrointestinal [65 cases vs. 43 cases;

RR ¼ 1.46 (1.0–2.13); p ¼ 0.05]

and breast cancers [18 cases vs. 11

cases; RR ¼ 1.65 (0.78–3.49);

p ¼ 0.15] with a 25% increase in

frequency of new cancers (15). Yet in

the meta-analysis conducted for this

trial for cancer-related endpoints (15)

and in the prespecified pravastatin

pooling program cancer incidence at

5 years in 21,000 patients and

112,000 patient years was unchanged

(16). Similarly long-term data from

the LIPID study at 8 years (17) and

4S (12) at 10 years showed no excess

cancers. While pooled data from the

atorvastatin studies is still awaited each

individual trial shows no excess of

cancers. There is no evidence for

excess cancer with lovastatin although

the trial database is limited. In this

issue, Stein et al. (18) present a

pooled analysis of all the major flu-

vastatin trials. In a group of 7801

patients with average exposure of

48 months to fluvastatin 20–80 mg is

associated with a 19% reduction in

total cancers (6.3% vs. 8%;

p ¼ 0.03). The only tumour that

may show an adverse effect in this

analysis is non-melanoma skin cancers

(3.6% vs. 4.6%; p ¼ 0.05) but the

numbers of events are small. There is

no association of LDL-C reduction

1022 EDITORIAL

ª 2006 The AuthorsJournal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, September 2006, 60, 9, 1021–1027