In a separate investigation, Gu et al.

(18)

from China

administered T undecanoate (500 mg) monthly for 30 months.

Using a primary outcome of pregnancy rate (PR), nine preg-

nancies were reported in

1,500 person-years of exposure

in the 24-month ef

ﬁ

cacy phase (855 men) for a cumulative

contraceptive failure rate of 1.1 per 100 men. Forty-three

participants (4.8%) did not achieve azoospermia or severe oli-

gozoospermia (

sperm/mL). Median time to onset of

azoospermia or severe oligozoospermia was 108 days. Sper-

matogenesis returned to the normal fertile reference range

in all but two participants. The median time to recovery of

spermatogenesis calculated from the beginning of the recov-

ery phase was 196 days. Recovery of sperm concentrations to

their own baseline values was 182 days and to normal sperm

output (

/mL) was 230 days. Most important, sper-

matogenesis recovered to normal reference levels (sperm con-

centration range, 0

–

/mL) in all but 17 participants

who completed the 12-month recovery period, and 15 of those

returned to normal reference levels at an extra 3-month

follow-up visit. Although this study has a follow-up period

of 2.5 years, it is important to note that longer term data

are not available in the published literature.

Liu et al.

(8)

performed an integrated, multivariate analysis

of 30 studies published between 1990 and 2005, in which se-

men analyses were monitored every month until recovery.

The primary outcome was the time for the sperm concentration

to recover to a threshold of 20 million/mL. Included were 1,549

healthy eugonadal men aged 18

–

51 years who were treated

with either androgens or androgens plus proestegens. The

strength of this large meta-analysis was

1,200 man-years

of treatment and

700 man-years of post-treatment recovery.

The median times for sperm to recover to thresholds of 20, 10,

and 3 million/mL were 3.4 months, 3.0 months, and 2.5

months, respectively. Higher rates of recovery were identi

ﬁ

with older age, Asian origin, shorter treatment duration,

shorter-acting T preparations, higher sperm concentrations at

baseline, faster suppression of spermatogenesis, and lower LH

levelsat baseline. It should be noted that the contraceptive trials

werein menofChineseethnicity and that extrapolationof

ﬁ

nd-

ings to men of non-Chinese ethnicities may not be reliable. In

addition, the use of T therapy in a broad population of men

may have varying results.

The typical probability of recovery to 20 million/mL was

67% within 6 months, 90% within 12 months, 96% within 16

months, and 100% within 24 months (

Table 1

). This observed

time to recovery may be helpful for patient counseling. It

should be cautioned that return of spermatogenesis may be

prolonged for a small number of men, which may be of signif-

icant concern with advanced maternal age. This study con-

cluded that hormonal male contraceptive regimens show

full reversibility within a predictable time course. It should

be noted that a signi

ﬁ

cant limitation of the published litera-

ture is a lack of pregnancy outcome data. Also, it is important

to emphasize that semen analysis data do not correlate with

pregnancy outcomes and that none of the literature assesses

time to fecundity.

THERAPEUTIC APPROACHES

For those hypogonadal men who desire to protect their future

fertility, exogenous T should be discouraged. As demon-

strated in the contraceptive trials, cessation of T therapy

may result in the restoration of baseline serum T levels.

However, these hypogonadal men may feel markedly symp-

tomatic and desire higher serum T levels. Rather than con-

tinue exogenous T therapy, a more appropriate approach in

these patients is to increase their own endogenous T. There

are several ways to accomplish this. However, all of these

methods, except for hCG injections, are considered off-label

uses and should be discussed in detail with our patients. The

underlying etiology of hypogonadism, especially regarding

modi

ﬁ

able causes needs to be evaluated before starting

treatments.

Selective Estrogen Receptor Modulators:

Clomiphene Citrate

Clomiphene citrate (CC) is a selective estrogen receptor (ER)

modulator

(19)

. This class of medications competitively binds

to ERs on the hypothalamus and pituitary gland (

Fig. 1

). As

a result, the pituitary sees less estrogen (E), and makes more

LH, which increases T production by the testes. Common dos-

ing starts at 25 mg orally every other day with upward titra-

tion to 50 mg daily, as needed. It is not as effective in

increasing serum T levels when LH and FSH levels are already

elevated, as seen in primary testis failure. At present, use of

hormonal dynamic testing, such as CC or hCG stimulation

test, are not well-de

ﬁ

ned or commonly used. Tamoxifen cit-

rate is another selective ER modulator. Potential side effects

include gynecomastia, weight gain, hypertension, cataracts,

and acne.

TABLE 1

Model-based probability of spermatogenic recovery to various threshholds.

Probability of recovery (%)

Within 6 months

Within 12 months

Within 16 months

Within 24 months

Individual baseline value

54 (46

–

60)

83 (75

–

89)

95 (89

–

98)

100

20 million/mL

67 (61

–

72)

90 (85

–

93)

96 (92

–

98)

100

10 million/mL

79 (73

–

83)

95 (92

–

97)

99 (97

–

100)

100

3 million/mL

89 (84

–

92)

98 (95

–

99)

100

Note:

Adapted from Liu PY et al. Lancet 2006;367:1412

–

20.

Con

ﬁ

dence interval could not be obtained from the model.

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

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VOL. 99 NO. 3 / MARCH 1, 2013

ORIGINAL ARTICLE: ANDROLOGY