Clomiphene citrate can be quite effective in increasing se-

rum T levels

(20, 21)

. In a study by Taylor and Levine

(22)

,CC

resulted in signi

ﬁ

cant increases in T levels from baseline, with

increases similar to those with T gel replacement therapy

(TGRT). One hundred four men began CC (50 mg every

other day) or TGRT (5 g of 1% gel). Average follow-up was

23 months (CC) versus 46 months (TGRT). Average post-

treatment T was 573 ng/dL (baseline, 277 ng/dL) in the CC

group and 553 ng/dL (baseline, 221 ng/dL) in the TGRT group.

They noted that the monthly cost of CC was about $190 less

than the cost of Testim 1% (5 g daily) at $270 (Auxilium Phar-

maceuticals, Inc.), and Androgel 1% (5 g daily) at $265 (Ab-

bott Laboratories). The CC represents a treatment option for

men with hypogonadism, demonstrating biochemical and

clinical ef

ﬁ

cacy with few side effects and lower costs than

TGRT.

In 2003, Guay et al.

(23)

observed an increase in free T

(

.001) in all 178 men with hypogonadism and erectile

dysfunction after treatment with CC for 4 months. Sexual

function improved in 75%, with no change in 25%. Responses

decreased signi

ﬁ

cantly with aging (

.05), diabetes, hyper-

tension, coronary artery disease, and multiple medication use.

Low-dose CC is also effective in improving the T/E

ratio

in men with hypogonadism

(24)

. In a small study, Shabsigh

et al.

(24)

administered CC (25 mg daily) to 36 hypogonadal

men with a mean age of 39 years. Mean pretreatment T and

estrogen levels were 247.6

39.8 ng/dL and 32.3

10.9

ng/dL, respectively. At 4

–

6 weeks, the mean T level increased

to 610.0

178.6 ng/dL (

.00001), whereas the T/E

ratio

improved from 8.7

–

14.2 (

.001).

More recently, Katz et al.

(3)

from the Memorial Sloan-

Kettering Cancer Center observed that long-term use of CC

was safe and effective in improving serum T levels to normal

(

Table 2

). In this moderately sized analysis, 86 men with hy-

pogonadism (T levels

300 ng/dL), aged 22

–

37 years, were

evaluated and treated for a mean duration of 19 months.

The CC was started at 25 mg every other day and titrated to

50 mg every other day. Target T level was 550 ng/dL. Once de-

sired T levels were achieved, T/gonadotopin levels were mea-

sured twice per year. In response to questions on the

Androgen De

ﬁ

ciency in Aging Males questionnaire, improve-

ments were reported in every area except for loss of height

(

Table 3

). There was signi

ﬁ

cant improvement in 5 of the 10

variables including decreased libido, lack of energy, decreased

life enjoyment, feeling sad/grumpy, and decreased sports per-

formance. During a long-term follow-up, this study demon-

strated that CC is an effective and safe alternative to T

supplementation therapy in men with hypogonadism.

A randomized, prospective trial of CC for hypogonadal

men with normal semen parameters is necessary to validate

the recommendation for the use of selective ER modulators

for fertility preservation. This study would need to demon-

strate that semen pro

ﬁ

les are not adversely affected. The CC

has been commonly used for the empiric treatment of male

infertility,

although

the

effect

can

variable

and

unpredictable.

Enclomiphene

A recently patented transisomer of clomiphene (Androxal;

Repros), potentially able to increase T yet maintain normal

semen quality, is currently being tested at 19 US sites (phase

3 trials ZA-301 and ZA-302). Preliminary results have been

positive, and this new treatment may be an especially impor-

tant and safe therapy for men with hypogonadism in their re-

productive years.

Human Chorionic Gonadotropin

Human chorionic gonadotropin is an LH analogue that stim-

ulates Leydig cell production of T and it can be derived from

urine as well as recombinant sources. Exogenous hCG in-

creases ITT concentrations and serum T levels. For men with

hypogonadotropic hypogonadism from anabolic steroid

abuse, administration of IM injections two to three times

per week at doses of 2,000

–

3,000 units for 4 months can ini-

tiate spermatogenesis

(25)

Human chorionic gonadotropin alone can maintain sper-

matogenesis for short periods of time. In a small case series by

Depenbusch et al.

(26)

, 13 azoospermic men with hypogona-

dotropic hypogonadism were initially administered hCG and

hMG to induce spermatogenesis. Human chorionic gonado-

tropin was then administered 500

–

2,500 IU SC twice weekly

alone for up to 2 years (range, 3

–

24 months). After 12 months,

sperm counts decreased gradually but remained present in all

patients, except for one who became azoospermic. The de-

creasing sperm counts indicate that FSH is essential for main-

tenance of quantitatively normal spermatogenesis.

High doses of hCG are not needed to stimulate and main-

tain spermatogenesis. Roth et al.

(27)

induced experimental

FIGURE 1

Clomiphene citrate (CC) works by blocking estrogen (E) at the

pituitary. The pituitary sees less E, and makes more LH. More LH

means that the Leydig cells in the testis make more T. (Adapted

from Craig Neiderberger, M.D.

http://urol.uic.edu/dept/niederberger.

php

and used with permission.)

Kim. Hypogonadism therapy in reproductive age men. Fertil Steril 2013.

VOL. 99 NO. 3 / MARCH 1, 2013

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Fertility and Sterility®