anastrozole. Men in both treatment groups had signi

ﬁ

cant

improvements in their T-to-E

ratios, sperm concentration,

morphology, and motility. In the small subset of 25 infertile

men receiving anastrozole for oligospermia, sperm concen-

tration increased signi

ﬁ

cantly from 5.5

–

15.6 million/mL,

and the total motile sperm concentration (TMSC) per ejaculate

increased from 833

–

2,931 million/mL (

.005). No change

was noted in the azoospermic cohort receiving anastrozole,

and no PRs were reported for any of the men in the study re-

gardless of semen parameter improvement.

In men with Klinefelter syndrome, aromatase inhibitors

have been used to treat hypogonadism before microscopic

TESE. Those men who responded to treatment (de

ﬁ

ned as

having a total T of

250 ng/dL) had a higher sperm retrieval

rate than men whose T level after treatment was

250 ng/dL

(77% vs. 55%)

(31)

In a recent study by Cakan et al.

(32)

, when anastrozole

was added to the treatment of 127 men with idiopathic

oligoasthenospermia who continued to demonstrate low T-

to-E

ratios after 3 months of therapy with tamoxifen alone,

increased sperm concentration and motility. Increased PRs

were also noted.

Letrozole, also a nonsteroidal third-generation aromatase

inhibitor, was recently shown by Saylam et al.

(33)

to be effec-

tive in infertile men with low serum T-to-E

ratios

10. Of the

10 men with oligospermia, the mean TMSC signi

ﬁ

cantly

increased from 6.4

2.7 to 15.7

5.01 million/mL after

treatment. Two of the 10 oligospermic men (20%) achieved

spontaneous pregnancy and 4 of 17 azoospermic men

(23.5%) were noted to have sperm in their ejaculate, with

a mean TMSC of 1.11

0.69 million/mL.

Extensive experience with third-generation aromatase

inhibitors in postmenopausal women has not revealed major

side effects related to their usage. Because elevations in liver

enzymes have been described in 7%

–

17% of patients, caution

should be taken in treating patients who have hepatic disease,

and liver function tests should be monitored. Other adverse

reactions include increases in blood pressure, rash, paresthe-

sias, malaise, aches, peripheral edema, glossitis, anorexia,

nausea/vomiting, and, rarely, alopecia that has spontane-

ously resolved. The prostate-speci

ﬁ

c antigen assessment

may be bene

ﬁ

cial in at-risk populations, as any form of ther-

apy for increasing serum T levels has the potential for increas-

ing prostate-speci

ﬁ

c antigen levels

(34, 35)

. The primary

concern associated with aromatase inhibitors in men is that

long-term E de

ﬁ

ciency may lead to osteopenia or osteoporosis

and ultimately have a negative effect on bone density.

Although most studies published to date describing use of

aromatase inhibitors in men did not appear to be associated

with adverse effects on bone, a recent study

(36)

demonstrated

a decrease in spinal bone mineral density after 1 year of anas-

trozole therapy in hypogonadal older men (mean age, 60

years). Long-term potentially detrimental effects of aroma-

tase inhibitors on bone health continue to be a concern and

have limited physician enthusiasm.

In conclusions, exogenous T supplementation decreases

sperm production. However, studies of hormonal contracep-

tion indicate that most men have a return of normal sperm

production within 1 year after discontinuing T supplementa-

tion. If at all possible, exogenous T use should be avoided in

men desiring future fertility given the potential for long-

term effects on spermatogenesis. Clomiphene citrate, an oral

selective ER modulator, is an off-label, but safe and effective

therapy for men who desire to maintain future potential fer-

tility. Although less frequently used in the general population,

hCG therapy with or without T supplementation represents an

alternative treatment. At present, routine use of aromatase in-

hibitors is not recommended based on a lack of long-term

data. Published literature to date is still limited, and this topic

will be a fertile area of interest in upcoming years, especially

regarding data on pregnancy outcomes.

Acknowledgments:

Special thanks to Carolyn Schum for

manuscript review and editing.

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