CHAPTER 64
Testosterone Deficiency
Robert Z. Edwards, MD
PATHOPHYSIOLOGY
The most important human androgen is testosterone.
Testosterone is a steroid hormone composed of 19 car-
bons (Fig. 64.1). Another prominent androgen is dehy-
droepiandrosterone (DHEA), which belongs to a group of
prohormones collectively referred to as 17-ketosteroids. In
adult males, the testes produce approximately 7 mg of tes-
tosterone per day.1 In females, the daily rate of testoster-
one production is approximately 0.25–0.3 mg.2 In males,
an additional 0.25 mg of testosterone is produced per day
in the adrenal glands, but the amount can vary depending
on the patient.3 In females, the adrenal glands contribute
to approximately 25% of daily testosterone production or
about 50–75 mcg/day, the ovarian contribution is 25%,
and the remaining 50% of daily testosterone production is
from peripheral conversion.2 The rest of the discussion will
be directed toward testosterone deficiency (TD) in men
and the mechanisms of control related to male physiology.
Testosterone is regulated by luteinizing hormone (LH)
from the anterior lobe of the pituitary gland. LH stimu-
lates the release of testosterone from the Leydig cells in the
testes. Sperm production is under the influence of follicle-
stimulating hormone (FSH), also released from the anterior
lobe of the pituitary gland. Testosterone inhibits the secre-
tion of LH by negative feedback.1 Testosterone plasma lev-
els follow a circadian rhythm, with the highest peak in the
early morning around 7:00 a.m. and another, smaller peak
in the afternoon around 4:00 p.m.4 However, the peak and
nadir of testosterone are not as dramatic as those of cortisol.
Testosterone is generally found in the body bound to
proteins, most specifically to the sex hormone–binding
globulin (SHBG). Testosterone bound to SHBG is mea-
sured as total testosterone (TT). SHBG production in the
liver is controlled by a number of hormones. Liver disease,
estrogen, and thyroid hormones increase SHBG. SHBG
decreases in response to androgens, insulin resistance and
diabetes, and in the presence of hypothyroidism.5 Plasma
SHBG levels tend to increase with increasing age. The
fraction of testosterone bound to SHBG in the serum is
proportional to the SHBG level.5 This helps explain the
faster rate of reduction of free testosterone (free T) com-
pared with TT (2%–3% per year decline compared with
1%–2%, respectively) after 40 years of age.
Diabetes, metabolic syndrome/insulin resistance, obesity,
and hypothyroidism can lead to falsely low TT despite nor-
mal free T levels. Checking free T is a more accurate test in
these individuals.
Testosterone can be converted to estradiol by aroma-
tase, especially in adipose tissue, and to dihydrotestosterone
630
(DHT) by 5-alpha reductase in specialized tissues such as
sebaceous glands, hair follicles, and prostate tissues (Fig.
64.2). Testosterone governs the development of second-
ary sex characteristics in the male. Sufficient testosterone
is essential for normal libido, fertility, and potency of
the male. It can also influence erythropoiesis. Testoster-
one exerts anabolic effects on muscularity and can affect
behavior and aggressiveness. Testosterone is metabolized
in the liver and primarily excreted in the urine.1
There are many clinical manifestations of TD, thereby
making diagnosis challenging. Physical symptoms
include decreased bone mineral density, decreased mus-
cle mass and strength, increased body fat or body mass
index (BMI), gynecomastia, anemia, axillary/genital hair
loss, and fatigue. Psychological symptoms may include
depressed mood, diminished energy/sense of vitality or
wellbeing, decreased self-confidence, and impaired cog-
nition/memory. Many times, however, men will pres-
ent with a chief complaint of sexual dysfunction. Sexual
symptoms include diminished libido, erectile dysfunc-
tion, difficulty in achieving orgasm, decreased morning
erections, and decreased sexual performance6 (Box 64.1).
While there is debate regarding what level of TT con-
stitutes deficiency, most experts agree that a healthy range
for TT is 300–1050 ng/dL when considering testosterone
replacement therapy.7,8 Data suggest that levels <440 ng/
dL are associated with elevated 10-year cardiovascular risk
in middle-aged and elderly men.8a There is general agree-
ment that free T or bioavailable T (free T plus albumin-
bound T) would provide a better estimation of T status;
however, there is concern about the reliability of these
assays and a general lack of research using these measures.
There is evidence of an excellent correlation between
saliva testosterone levels and free T levels obtained simul-
taneously.9 This may prove to be a reliable alternative to
serum testing; however, some of the same concerns men-
tioned previously remain. A single low AM testosterone
level should be repeated to confirm the diagnosis of TD.
Much of our current data on the normal changes in adult
testosterone levels related to aging are from the Massa-
chusetts Male Aging Study (MMAS). This study followed
men over 3 decades. At the beginning of the study in 1987,
there were 1667 participants, and by the end of the study in
2004, there were 584 participants remaining. Longitudinal
data revealed an average of 1%–2% TT decline per year,
with a more rapid decline in free T due to the increases in
SHBG with aging as discussed previously.5,10 Interestingly,
there was variability in the rate of decline with some sub-
jects’ TT levels not declining over time and a few partici-
pants had increases with age. The mean TT level at 45 years
old was approximately 540 ng/dL, while it dropped down to
approximately 440 ng/dL by 70 years old.5 The prevalence