gonadotropin de

ﬁ

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 (

.001). In addition, serum

hCG was signi

ﬁ

cantly correlated with both ITT and serum T

(

.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

ﬁ

ciency. Although hCG injections may be

bene

ﬁ

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

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-

ﬁ

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

ﬁ

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-

ﬁ

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

. 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

ﬁ

cally, ar-

omatase inhibitors may have greater bene

ﬁ

t than anti-Es in

men with lower serum T-to-E

ratios (

10) and in obese

patients.

Classically, aromatase inhibitors have been classi

ﬁ

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

levels in men and actually decreases the plasma E

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

ﬁ

le.

Aromatase inhibitors have been used to treat men with

conditions including idiopathic male infertility, primarily

men with lower serum T-to-E

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

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 (%)

value

Decreased libido

.01

Lack of energy

.01

Decreased strength/endurance

.18

Lost height

.45

Decreased life enjoyment

.001

Sad/grumpy

.01

Erections weaker

.29

Decreased sports performance

.001

Sleep after dinner

.17

Decreased work performance

.28

Note:

Adapted from Katz DJ et al. British Journal of Urology 2012;110:573

–

8. ADAM

Androgen De

ﬁ

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

ﬁ

les.

Baseline,

mean (±SD)

After treatment,

mean (±SD)

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

(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

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