Testosterone therapies have been increasingly used in ag-

ing men, as well as in men of reproductive age. Compared to

the 1970s, men are fathering children at an older age. Com-

bined with the maturation of the Baby Boomer population,

it is anticipated that there may be a signi

ﬁ

cant increase in

hypogonadal, aging men desiring to father children. The

treatment of hypogonadism requires symptomatology, as

well as low serum T levels, generally regarded to be around

300 ng/dL. With the recent introduction of several newer

commercial T preparations and an increased public awareness

of androgen de

ﬁ

ciency syndromes, use of hormone replace-

ment therapies has been increasing. During the past 5 years

there has been an increase in T prescriptions by 170%

(7)

However, men desiring to maintain their reproductive poten-

tial may not be fully aware of the risks of exogenous T

therapy.

Many T users/abusers and clinicians are unaware of the

fact that the use of exogenous T has been shown to suppress

the hypothalamic-pituitary-gonadal axis and result in

infertility. Physicians need to educate their patients about

the potentially deleterious effects exogenous T can have on

spermatogenesis and on fertility. The use of IM T has been in-

vestigated as a male contraceptive agent

(8)

T REPLACEMENT THERAPY INHIBITS

SPERMATOGENESIS

Mechanisms

T inhibits GnRH and gonadotropin secretion. Exogenous

administration of synthetic T results in negative feedback

on the hypothalamic-pituitary axis, inhibiting GnRH, and,

thus, inhibition of the secretion of FSH and LH. Suppression

of gonadotropins results in a decrease in intratesticular T

(ITT) levels and overall T production. Normally, ITT concen-

trations are roughly 50

–

100 times serum levels. Exogenous

T therapies can suppress ITT production to such a degree

that spermatogenesis can be dramatically compromised at

ITT concentrations to less than 20 ng/mL

(9)

. Intratesticular

T is an absolute prerequisite for normal spermatogenesis.

Complete inhibition of ITT can result in azoospermia

(10, 11)

In men using anabolic steroids, despite normal-to-high

serum androgen concentrations, ITT concentrations neces-

sary to maintain spermatogenesis may be lacking. Many

male users of anabolic steroids develop hypogonadotropic

hypogonadism with subsequent testicular atrophy. Anabolic

steroid use commonly results in oligozoospermia or azoosper-

mia along with abnormalities of sperm motility and morphol-

ogy

(12, 13)

Recovery of Spermatogenesis after Exogenous T

Use

Rates of success in recovering spermatogenesis after use of

exogenous T are generally quite favorable. The

ﬁ

rst strategy

that should be used for the hypogonadal male interested in fa-

thering children is the cessation of use of exogenous T. A

study by the World Health Organization Task Force evaluated

271 men who received 200 mg of T enanthate weekly

(14)

. Af-

ter 6 months, 157 (65%) of the men were azoospermic. The

mean time to azoospermia was 120 days. After 6 months of

treatment, the patients entered the recovery phase. Although

84% of men were able to achieve a sperm density

20 mil-

lion/mL after a median of 3.7 months, only 46% of patients

were able to achieve their baseline sperm density.

Mills

(15)

evaluated the recovery of spermatogenesis after

exogenous T administration in 26 men with a recent history of

anabolic steroid use. In this relatively small study, all men

who discontinued exogenous T usage were treated with hCG

3,000 units IM every other day for a minimum of 3 months.

Of the two men who remained azoospermic, one had insuf

ﬁ

cient follow-up and the other was suspected of continued

anabolic steroid use. Men who were using IM T at the time

of presentation recovered spermatogenesis in an average of

3.1 months. However, men receiving transdermal T supple-

mentation at the time of presentation took an average of

7.4 months. Mills

(15)

concluded that impairment of fertility

after T replacement therapy suppression is reversible and

that the rate of sperm may be related to the delivery system.

The published literature represents the best available

evidence regarding the recovery of spermatogenesis after T

supplementation. However, the preponderance of the litera-

ture re

ﬂ

ects results with the use of T therapy as a male contra-

ceptive agent. This situation may very well not be re

ﬂ

ective of

the hypogonadal male seen in clinical practice. The caveat is

that the consistency of spermatogenesis recovery in clinical

practice may not be as predictable as seen in contraceptive

studies.

T as a Male Contraceptive

Pharmaceutical companies have tried to develop hormonal

male contraceptives with the intent of causing a withdrawal

ofthe gonadotropin supporttothe testis withresultant suppres-

sion of spermatogenesis and ITT

(16)

.Tes

tos

ronehasbeen

studied alone, as well as in combination with progestagens

(16)

. Testosterone used as a contraceptive agent is a good model

to determine the effect and time to recovery with cessation of T

treatment. These trials have not examined the use of agents to

promote recovery of natural T or spermatogenesis.

A study by Wang et al.

(17)

found that oligozoospermia

induced by exogenous T was associated with normally func-

tioning spermatozoa. Data were analyzed from eight subjects

whose sperm concentrations were between 1.3 and 10

mL at the suppression phase. Testosterone enanthate (200 mg)

was administered IM weekly during the suppression and T

treatment (ef

ﬁ

cacy) phases (total 15 months). Sperm function

tests were performed during the pretreatment, during sup-

pression (usually after 6

–

10 weeks of treatment, when sperm

concentration was anticipated to decrease to

10 million/

mL), and during recovery phases. Investigators found that

the sperm concentration was reduced, but sperm motility, mo-

tility characteristics, and morphology were not affected by T

enanthate treatment. The residual spermatozoa in the ejacu-

late exhibited normal hyperactivation, could acrosome react,

and maintained the capacity to penetrate and fuse with the

oocyte. The investigators concluded that suppression of sper-

matogenesis to moderate oligozoospermia (

10 million/mL)

with exogenous T was not associated with impaired sperm

function.

VOL. 99 NO. 3 / MARCH 1, 2013

719

Fertility and Sterility®