gonadotropin de
ï¬
ciency in 37 normal men with the GnRH
antagonists and randomized them to receive one of four
low doses of hCG: 0, 15, 60, or 125 IU SC every other day
or 7.5g daily T gel for 10 days. Testicular
fl
uid was obtained
by percutaneous aspiration for steroid measurements at base-
line, and after 10 days of treatment. The ITT concentrations
increased in a dose-dependent manner with very low-dose
hCG administration from 77
–
923 nmol/L in the 0-IU and
125-IU groups, respectively (
P
<
.001). In addition, serum
hCG was signi
ï¬
cantly correlated with both ITT and serum T
(
P
<
.01). They concluded that doses of hCG far lower
than those used clinically increase ITT concentrations in
a dose-dependent manner in normal men with experimental
gonadotropin de
ï¬
ciency. Although hCG injections may be
bene
ï¬
cial in increasing serum T levels and preserving fertil-
ity, hCG injections can be costly, and the invasive nature of
this medication can also be a deterrent.
hCG
D
T
Low-dose hCG with IM T enanthate (200 mg/wk) can main-
tain ITT and serum T levels
(28)
. The use of hCG with IM T
was initially studied for the development of a male contracep-
tive agent. Coviello et al.
(28)
administered low doses of hCG
(0, 125, 250, or 500 IU every other day) to normal men during
this 3-week study, and measured serum and ITT levels. Al-
though the administration of T alone resulted in profound de-
creases in ITT concentrations (94% from baseline in the T
enanthate and placebo hCG group), the addition of low-
dose hCG resulted in maintenance of the ITT levels. The
mean baseline ITT concentration for all 29 participants before
treatment (1,174
±
79 nmol/L) was approximately 80-fold
higher than that of serum T (14.1
±
1.1 nmol/L). Although se-
rum T increased from baseline in all groups, ITT remained sig-
ni
ï¬
cantly higher than serum T in all four groups after
treatment. Despite supraphysiologic doses of exogenous T,
high levels of ITT can be maintained with the low-dose hCG.
Avila et al.
(29)
studied the effect of hCG administration
with T replacement therapy on spermatogenesis. In this small
series, 10 men received short-acting T preparations in addi-
tion to low doses of hCG. The key
ï¬
nding of this study was
that on the basis of semen analyses, spermatogenesis was es-
sentially maintained. Although there was a minimal decline
in sperm density, no men developed azoospermia. Low-dose
hCG with T supplementation can maintain production of
ITT and spermatogenesis. There are no fecundity data. The
substantial cost and need for frequent hCG injections are sig-
ni
ï¬
cant barriers to the use of this combination, especially
when alternative therapies are available.
Aromatase Inhibitors (Anastrozole and Letrozole)
Aromatase is a cytochrome P-450 enzyme concentrated in the
testes, liver, brain, and adipose tissue and is responsible for
the conversion of T to E
2
. Estradiol inhibits gonadotropin se-
cretion and may exert direct effects on ITT production. Aro-
matase inhibitors function by blocking the conversion of
androgens to E, consequently increasing serum levels of LH,
FSH, and T and resulting in functional effects similar to those
of the anti-Es. This class of drugs has been used to improve
male fertility and stimulate spermatogenesis. Speci
ï¬
cally, ar-
omatase inhibitors may have greater bene
ï¬
t than anti-Es in
men with lower serum T-to-E
2
ratios (
<
10) and in obese
patients.
Classically, aromatase inhibitors have been classi
ï¬
ed as
either steroidal or nonsteroidal. The nonsteroidal late-
generation aromatase inhibitors, such as anastrozole and
letrozole, are very potent and do not block other steroidogenic
enzymes, therefore adrenal steroid supplementation is not re-
quired. Although aromatase inhibition by these two agents is
close to 100%, their administration does not completely sup-
press E
2
levels in men and actually decreases the plasma E
2
-
to-T ratio by 77%. This incomplete suppression may be related
to the high levels of circulating T in men and may provide an
advantage by limiting the adverse side effect pro
ï¬
le.
Aromatase inhibitors have been used to treat men with
conditions including idiopathic male infertility, primarily
men with lower serum T-to-E
2
ratios (
<
10), and men with hy-
pogonadism, often related to obesity. They also have been
used for normalization of serum T levels before microscopic
testicular sperm extraction (TESE) in men with Klinefelter
syndrome.
Raman and Schlegel
(30)
reported on infertile men with
T-to-E
2
ratios (
<
10) treated with either testolactone or
TABLE 3
Alterations in individual symptoms after clomiphene citrate therapy
based on the ADAM questionnaire.
Baseline
(%)
After
treatment (%)
P
value
Decreased libido
72
32
<
.01
Lack of energy
65
40
<
.01
Decreased strength/endurance
28
21
.18
Lost height
4
5
.45
Decreased life enjoyment
85
40
<
.001
Sad/grumpy
60
30
<
.01
Erections weaker
12
8
.29
Decreased sports performance
55
25
<
.001
Sleep after dinner
34
28
.17
Decreased work performance
45
38
.28
Note:
Adapted from Katz DJ et al. British Journal of Urology 2012;110:573
–
8. ADAM
¼
Androgen De
ï¬
ciency in Aging Males.
Kim. Hypogonadism therapy in reproductive age men. Fertil Steril 2013.
TABLE 2
The effect of clomiphene citrate on serum hormone pro
ï¬
les.
Baseline,
mean (±SD)
After treatment,
mean (±SD)
P
value
Total T (ng/dL)
192 (B7)
485 (165)
<
.01
Free T (pg/mL)
22 (16)
95 (35)
<
.01
SHBG (nM/L)
30 (12)
32 (15)
.72
E
2
(pg/mL)
26 (22)
39 (19)
<
.05
LH (IU/mL)
2.6 (2.2)
6.8 (2.9)
<
.01
FSH (IU/mL)
1.9 (1.7)
7.6 (1.9)
<
.01
Note:
Adapted from Katz DJ et al. British Journal of Urology 2012;110:573
–
8. SHBG
¼
sex
hormone-binding globulin.
Kim. Hypogonadism therapy in reproductive age men. Fertil Steril 2013.
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VOL. 99 NO. 3 / MARCH 1, 2013
ORIGINAL ARTICLE: ANDROLOGY