Clomiphene citrate can be quite effective in increasing se-
rum T levels
(20, 21)
. In a study by Taylor and Levine
resulted in signi
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
cacy with few side effects and lower costs than
In 2003, Guay et al.
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
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
in men with hypogonadism
. In a small study, Shabsigh
et al.
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
ng/dL, respectively. At 4
6 weeks, the mean T level increased
to 610.0
178.6 ng/dL (
.00001), whereas the T/E
improved from 8.7
14.2 (
More recently, Katz et al.
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
ciency in Aging Males questionnaire, improve-
ments were reported in every area except for loss of height
Table 3
). There was signi
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
les are not adversely affected. The CC
has been commonly used for the empiric treatment of male
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
Human chorionic gonadotropin alone can maintain sper-
matogenesis for short periods of time. In a small case series by
Depenbusch et al.
, 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.
induced experimental
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.
and used with permission.)
Kim. Hypogonadism therapy in reproductive age men. Fertil Steril 2013.
VOL. 99 NO. 3 / MARCH 1, 2013
Fertility and Sterility®