REVIEW

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Drug Insight: recent advances in male hormonal

contraception
John K Amory*, Stephanie T Page and William J Bremner

INTRODUCTION

S U M M A RY
As there are limitations to current methods of male contraception, research
has been undertaken to develop hormonal contraceptives for men,
analogous to the methods for women based on estrogen and progestogens.
When testosterone is administered to a man, it functions as a contraceptive
by suppressing the secretion of luteinizing hormone (LH) and folliclestimulating hormone (FSH) from the pituitary gland. Since these
hormones are the main stimulatory signals for spermatogenesis, low levels
of LH and FSH markedly impair sperm production. After 34 months
of testosterone treatment, 6070% of men no longer have sperm in their
ejaculate, and most other men exhibit markedly diminished sperm counts.
Male hormonal contraception is well tolerated, free of serious adverse side
effects, and 95% effective in the prevention of pregnancy. Importantly,
male hormonal contraception is reversible, with sperm counts usually
recovering within 4 months of the discontinuation of hormone treatment.
Because exogenous testosterone administration alone does not completely
suppress sperm production in all men, researchers have combined
testosterone with second agents, such as progestogens or gonadotropinreleasing-hormone antagonists, to further suppress secretion of LH
and FSH and improve suppression of spermatogenesis. Recent trials
have used combinations of long-acting injectable or implantable forms
of testosterone with progestogens, which can be administered orally,
by injection or by a long-acting implant. Such combinations suppress
spermatogenesis to zero without severe side effects in 8090% of men, with
near-complete suppression in the remainder of individuals. One of these
testosterone and progestogen combination regimens might soon bring the
promise of male hormonal contraception to fruition.
KEYWORDS male fertility, progesterone, spermatogenesis, testosterone

REVIEW CRITERIA
We searched PubMed for publications using the following search terms: male
contraception, male hormonal contraception, male pill, male infertility,
gonadotropin suppression, azoospermia and contraceptive efficacy. All
relevant articles were English-language papers published in the last 30 years.

JK Amory is an Associate Professor of Medicine, ST Page is an Acting Instructor

in Medicine and WJ Bremner is a Professor of Medicine and the Chairman of
the Department of Medicine, University of Washington, Seattle, WA, USA.
Correspondence
*Box 356429, University of Washington,1959 NE Pacific Street, Seattle, WA 98195, USA
jamory@u.washington.edu
Received 19 August 2005 Accepted 28 October 2005
www.nature.com/clinicalpractice
doi:10.1038/ncpendmet0069

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Despite currently available contraceptives,

the worlds population exceeds 6 billion and
is increasing by 80 million yearly.1 In many
parts of the world, overpopulation is a leading
cause of human suffering and environmental
degradation. Much of this population growth
is unintended. Family-planning organizations estimate that half of all conceptions are
unplanned and half of the resulting pregnancies
are undesired.2 This high rate of unintended
pregnancy is due to inadequate access to or use
of contraceptives, or both. Inadequate contraception leads to undesired pregnancies and
high rates of abortion, or results in unwanted
children who suffer disproportionately from
poverty and neglect.3 There is therefore a great
need for better access to existing contraceptives,
better contraceptive education, and more
contraceptive options.
In particular, male-directed contraceptive
options are extremely limited, consisting of
only condoms or vasectomy. Despite this,
men currently account for a third of all
contra ceptive use. 4 Because condoms and
vasectomy each have shortcomings, research
into the development of a hormonal contraceptive for men analogous to the estrogen
and progesterone pill used so successfully
by women has been undertaken. A male
hormonal contraceptive has the potential
to be safe, effective and, in contrast to vasectomy, reversible when fertility is desired. The
appeal of a male hormonal contraceptive to
men is great. In surveys, a majority of men
indicate a willingness to use such a male
hormonal contraceptive if one were available,5,6 and 98% of women in stable relationships would be willing to rely on their male
partner to use such a method.7 In this article,
we will review the mechanism of action and
efficacy of experimental hormonal male
contraception, with particular emphasis on
newer regimens that are nearing introduction
to clinical practice.

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TESTOSTERONE AND ITS MECHANISM

OF ACTION

CONTRACEPTIVE EFFICACY

Most studies of male hormonal contraceptives

examine the effect of exogenous hormones on
sperm production. The best test of a contraceptive,
however, is to study the agent in couples who

JANUARY 2006 VOL 2 NO 1 AMORY ET AL.

Exogenous testosterone
+ progestogens

Hypothalamus

GnRH

GnRH antagonists

Pituitary

FSH

Sertoli cell
Testicle

It has been known for over 65 years that the

chronic administration of testosterone to a man
suppresses sperm production.8 Testosterone
functions as a contraceptive by suppressing
the secretion of luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) from the
pituitary. Low levels of LH and FSH deprive
the testis of the stimulatory signals required for
spermatogenesis, leading to markedly decreased
sperm counts and infertility in most, but not all,
men (Figure 1). Because the administration of
testosterone alone fails to completely suppress
sperm production in some men, PROGESTOGENS
or gonadotropin-releasing hormone (GnRH)
antagonists are combined with testosterone to
further suppress pituitary gonadotropins and
improve its contraceptive efficacy.
In normal men, sperm counts vary from
20200 million sperm per ml of ejaculate.
The absence of spermatozoa in the ejaculate, a condition called azoospermia, makes
fertilization impossible. In most trials of male
hormonal contraception a majority of men
have sperm counts suppressed to azoospermia;
however, some men have a partial reduction in their sperm counts, a condition called
oligozoospermia. Male hormonal contraceptives inhibit sperm production and do not
incapacitate existing sperm. As spermatogenesis
takes place over 72 days, there is a delay of 2
3 months in the onset of the full contraceptive
effect associated with use of male hormonal
contraceptives, a delay that is similar to that seen
with vasectomy but longer than the period of
time required for female oral contraceptives to
be effective. In addition, there are ethnic differences in the response of sperm counts to male
contraceptive regimens. For example, study
volunteers in Asia exhibit rates of azoospermia
in the 90100% range on testosterone-alone
regimens, whereas non-Asian men have rates
of azoospermia closer to 60% with the same
treatment.9,10 Although the explanation for this
difference is unknown, it complicates extrapolation of rates of suppression of sperm counts
between populations.

Cortex

LH

Leydig cell

Mature
sperm
Seminiferous tubule

Testosterone
Testicular interstitium

Figure 1 The endocrinology of spermatogenesis and male hormonal

contraception. Solid arrows denote promotion of spermatogenesis; dashed
lines denote inhibition of spermatogenesis.
FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone;
LH, luteinizing hormone.

use it as a sole means of contraception. Four

such male hormonal contraceptive efficacy trials
have been published.9,1113 The first of these
tested only the fertility of men who became
azoospermic with testosterone administration;9
it demonstrated that the contraceptive efficacy
of testosterone-induced azoospermia is almost
perfect. This study cannot be used to determine
the overall efficacy of testosterone as a contraceptive, however, as men who did not achieve
azoospermia were not allowed to enter the
efficacy-assessment phase.
The three more-recent trials have examined
the outcomes of all subjects enrolled and allowed
men whose sperm counts were suppressed below
a threshold of 15 million sperm/ml to use the
method as a sole means of birth control.1113
Analysis of these studies reveals that male
hormonal contraception is associated with a low
incidence of pregnancy and an overall efficacy
of approximately 95%, even when men whose
sperm production is incompletely suppressed
are included (Table 1). This overall figure is

GLOSSARY
PROGESTOGENS
Any substance having
progesterone-like activity
and leading to the
suppression of the secretion
of pituitary gonadotropins

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Table 1 Male hormonal contraceptive efficacy trials.

Study
(year published)

Number
of
couples

Number (%) of
azoospermic
men

Number (%) of
oligozoospermic
men

Number (%)
of failures to
suppressa

Number
(%) of
pregnancies

Total
number (%)
of failuresb

Overall
contraceptive
efficacy (95% CI)

WHO (1996)11

357

268 (75)

81 (23)

8 (2.2)

11 (3.1)

19 (5.3)

94.7 (9297)

305

130 (43)

166 (54)

9 (2.9)

1 (0.3)

10 (3.3)

96.7 (9598)

53

49 (93)

2 (3.6)

2 (3.6)

0 (0.0)

2 (3.6)

96.4 (91100)

715

447 (62)

249 (35)

19 (2.6)

12 (1.7)

31 (4.4)

95.7 (9497)

Gu et al.

(2003)12

Turner et al.
Total

(2003)13

aDefined as a sperm count of less than 35 million sperm/ml depending on study. bDefined as pregnancy and/or failure to suppress to threshold for enrollment in
the efficacy phase.

only slightly inferior to the efficacy of female

hormonal contraceptives. In these studies, a
sperm count below 1 million sperm/mlsevere
oligozoospermiais associated with a risk of
pregnancy of approximately 1%.11 Therefore,
uniform suppression of all subjects to a sperm
count below 1 million sperm/ml is thought
to be a reasonable short-term goal for male
contraceptive development.14
TESTOSTERONE ENANTHATE

The WHO conducted two important studies

into male hormonal contraceptives. These trials
used the injectable testosterone ester, testosterone enanthate (TE), as a single agent for male
contraception. The first study enrolled 271 men
who were administered 200 mg TE by weekly
injection for 6 months.9 On this regimen, 65%
of the men became azoospermic after a mean
of 4 months. In addition, 75% of the remaining
men had sperm counts suppressed to less than
3 million sperm/ml. The investigators went on to
test the fertility of 119 of the azoospermic men in
a 12-month efficacy phase in which these couples
used the TE injections as their sole means of
birth control. Only one pregnancy occurred in
these couples, corresponding to a pregnancy
rate of 0.8 pregnancies per 100 person-years, an
efficacy rate of over 99%.
The second WHO study tested the fertility of
men who became either azoospermic or oligozoospermic (less than 35 million sperm/ml)
on 200 mg of TE weekly.11 The study enrolled
399 men, all but 8 (2%) of whom became
azoospermic or oligozoospermic and met
criteria for entry into the efficacy phase of the
study. In this phase, there were no pregnancies
fathered by the men who became azoospermic.
In men whose sperm counts were suppressed
to below 35 million sperm/ml, fertility was

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reduced to 8.1 pregnancies per 100 personyears. The fertility rate for all men whose sperm
counts were suppressed enough to enter the efficacy phase was 1.4 pregnancies per 100 personyears, and the overall failure rate (including
the eight men whose sperm counts were not
suppressed to less than 5 million sperm/ml)
was 5.3% for an overall contraceptive efficacy
of 94.7% (Table 1). All subjects had return of
normal sperm production 46 months after the
injections were discontinued.
These two landmark studies demonstrated
that a regimen of weekly TE injections is a safe,
reversible and effective contraceptive in the
large majority of men. The main drawbacks are
the delay in onset of full contraceptive action
of 34 months, and the fact that in 2% of men,
the sperm count was not suppressed below
3 million sperm/ml and they therefore remain
fertile. In addition, the use of weekly intramuscular injections in this regimen led a small
number of men to discontinue involvement.
Side effects from weekly TE included weight
gain, a reversible 25% reduction in testicular
volume and a 10% decrease in serum HDL
cholesterol.15,16 Importantly, there is no
evidence that exogenous testosterone administration increases the risk of blood clotting, which
could increase the risk of heart attack or stroke.
Indeed, one study suggests that the administration of exogenous testosterone in a male contraceptive regimen can elicit an antithrombotic
effect.17 Quality of life and wellbeing are maintained on male contraceptive regimens.18 With
regard to sexual function, the use of male
hormonal contraception can be associated
with slight improvements in the frequency of
intercourse. Overall, the TE regimen was rated
better than expected by the majority of men in
these studies.19

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TESTOSTERONE UNDECANOATE

Testosterone undecanoate (TU) is a long-chain

ester that can be administered orally or by injection for androgen therapy.20 In testosteronedeficient men, a single injection maintains
serum testosterone levels in the normal range for
612 weeks.21,22 The first small trial using TU
injections in normal men for male contraception
was conducted in China23 and two subsequent
trials were performed in Germany.24,25 In
the initial Chinese study, volunteers received
monthly doses of 500 mg or 1,000 mg TU.
Azoospermia occurred in 11 of the 12 men in the
500 mg group and all 12 in the 1,000 mg group,
with the 1,000 mg group achieving azoospermia
more quickly.
Subsequently, a large Chinese efficacy trial
studied 308 men treated with monthly injections
of 500 mg TU after a 1,000 mg loading dose.12
This regimen resulted in azoospermia in 43%
of men, and only nine (3%) of the men maintained sperm counts above 3 million sperm/ml.
In a 12-month contraceptive-efficacy phase of
the study, 296 couples used the TU injections
as a sole means of contraception. Of these, six
men had partial return of sperm production
and there was one pregnancy attributed to the
reappearance of sperm while on TU therapy.
Overall, this regimen has a 96.7% contraceptive
efficacy in Chinese men (Table 1).
In the German studies,24,25 TU was studied
alone or with addition of a progestogen (see
below). In the arm of the study in which
subjects received only TU, 8 out of 14 men
who were administered 1,000 mg TU every
6 weeks achieved azoospermia, with 4 of the
remaining 6 having sperm counts suppressed
below 3 million sperm/ml. Although the regimens and formulations of TU were slightly
different, it appears that, as was the case with
TE, it remains more difficult to suppress sperm
counts in non-Asian populations even with
long-acting androgens such as TU.
COMBINATION OF TESTOSTERONE
AND PROGESTOGENS

Since progestogens inhibit the secretion of FSH

and LH from the pituitary, several progestogens have been combined with testosterone to
improve its contraceptive effect by augmenting
suppression of gonadotropins. Such a combination also allows for reduction in the amount of
testosterone required for effective contraception.
In addition, it has been hypothesized that

JANUARY 2006 VOL 2 NO 1 AMORY ET AL.

progestogens might also have a direct inhibitory

effect on spermatogenesis. One recent study in
a primate model, however, has not found such
an effect for the progestogen noresthisterone.26
One drawback to the use of progestogens in
men is the possibility of side effects such as
weight gain and additive suppression of serum
HDL cholesterol.
Regimens using testosterone plus progestogens
were first tested for male hormonal contraception in the 1970s.27 It was demonstrated that
combinations of TE and medroxyprogesterone
acetate could induce azoospermia in half of the
subjects, with some degree of oligozoospermia
in most others.28 Unfortunately, the contraceptive efficacy of these combinations was poor,
with case reports of nine couples conceiving
while on therapy despite the simultaneous use
of other methods of contraception; all conceptions occurred while sperm counts were under
10 million sperm/ml.29
Many subsequent studies of progestogens
have focused on oral compounds, such as levonorgestrel. A randomized, controlled trial of
0.5 mg levonorgestrel with 100 mg of weekly
TE showed that the combination was superior to TE alone in achieving azoospermia by
6 months (67% versus 33%).30 Furthermore,
the proportion of subjects achieving a sperm
count of less than 3 million sperm/ml was
94% in the combination group compared with
61% in the TE-alone group. Drawbacks to the
combination regimen included greater weight
gain and further decreases in HDL cholesterol
when compared with the TE-alone group. Much
lower doses of levonorgestrel have subsequently
been demonstrated to be as effective at achieving
azoospermia, while minimizing the weight gain
and reductions of HDL cholesterol seen with the
higher doses.31,32 Recently, the combination of a
long-acting levonorgestrel implant and 1,000 mg
of TU every 8 weeks resulted in azoospermia in
90% of Chinese men, with all subjects undergoing suppression to sperm counts below
3 million sperm/ml.33 This combination is
currently undergoing large-scale efficacy studies
in China.
Another progestogen, desogestrel, has
been tested in male contraceptive regimens
with injectable TE34,35 or testosterone pellets
(400 mg implanted every 12 weeks),36,37 with
overall rates of azoospermia in the 8090%
range in mostly non-Asian populations. The
active metabolite of desogestrel is etonogestrel,

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which has also been studied in combination

with intramuscular injections at 4-week or
6-week intervals of the testosterone ester, testosterone decanoate (TD). In a large study of 112
subjects, the sperm counts of 111 men were
suppressed to less than 1 million sperm/ml.38
Suppression was more rapid in the group
receiving TD injections every 4 weeks, and side
effects were minor.
Enthusiasm for this combination has led to two
studies combining etonogestrel implants with
testosterone. In the first, implanted etonogestrel
rods (Implanon, Organon, The Netherlands)
were combined with testosterone pellets and
resulted in azoospermia in 10 out of 14 men,
with 13 out of 14 men having sperm counts of
less than 1 million sperm/ml after 24 weeks.39
Importantly, there were no significant reductions in HDL cholesterol when the progestogen
was administered via implant, implying that
this might be a preferable route for long-term
administration of these compounds.
These results were promising enough for
a large pharmaceutical company to sponsor a
multi-center phase II study of the combination
of Implanon with TD given by intramuscular
injection every 46 weeks.40 This combination
achieved rates of azoospermia in the 8090%
range, with high overall acceptability and a low
incidence of side effects. A follow-up trial of
Implanon combined with TU (which exhibits
a half-life superior to that of TD) and involving
more than 300 subjects is currently underway
at several European centers. If this trial is also
successful, it seems likely the combination
of Implanon and TU could become the first
marketed male hormonal contraceptive, possibly
reaching the market within 10 years.
Progestogens with antiandrogenic properties, such as cyproterone acetate,41 have been
combined with testosterone as potential male
contraceptives. The antiandrogenic effect of
cyproterone might allow it to interfere with
testosterone-mediated spermatogenesis in the
testis in addition to its progestogenic inhibition of FSH and LH secretion from the pituitary. In one small trial, all men receiving oral
cyproterone acetate and 100 mg weekly TE
became azoospermic, whereas only three
out of five in the TE-alone group attained
azoospermia.42 In addition, the time required to
achieve azoospermia in the cyproterone groups
was half of that needed in the testosterone-alone
group (49 versus 98 days).

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Subsequently, these researchers have tested

lower doses of cyproterone acetate,43 and
even combined cyproterone with oral TU in a
completely oral male contraceptive regimen.44 In
this study, cyproterone was combined with oral
TU twice daily, with sperm counts in six out of
eight men suppressed below 3 million sperm/ml,
and those of the two remaining subjects
suppressed to 4 million and 6 million sperm/ml.
Unfortunately, cyproterone is not available in
some countries (including the US); however, a
similar antiandrogenic progestogen, dienogest,
might be a promising progestin for future clinical
trials in male contraception.45
The long-acting injectable progestogen,
norethisterone enanthate, has also been tested
in male hormonal contraceptive trials.46 In one
study, 13 out of 14 men who received the combination of 1,000 mg TU and 200 mg norethisterone
every 6 weeks achieved azoospermia after 32
weeks of treatment, with HDL suppression and
mild weight gain in line with prior studies of
combinations of testosterone and progestogen.47
It has subsequently been demonstrated that high
rates of azoospermia (90%) can be maintained
when TU and norethisterone enanthate are
administered at 8-week intervals, but not when
doses are given every 12 weeks.48 Nevertheless,
this approach is a significant improvement over
the requirement for weekly injections of TE in
most prior studies. Alternatively, norethisterone
enanthate can also be administered orally in
combination with injectable TU.49
Medroxyprogesterone acetate, first used in
the 1970s in male contraceptive studies, has
re-emerged in two more-recent male contraceptive studies. The first was an Australian
study combining medroxyprogesterone, given
by intramuscular injection every 12 weeks, with
testosterone pellets administered by implantation every 46 months.13 In this study, 53 out
of 55 men achieved sperm counts of less than
1 million sperm/ml and entered a 12-month
efficacy phase, in which no pregnancies were
observed (Table 1). This important trial is the
first study of testosterone and progestogen
efficacy and confirms that the high rate of
pregnancy prevention observed in the original WHO studies extends to testosterone and
progestogen combinations.
Additionally, a trial of TU at a dose of 1,000 mg
every 8 weeks with medroxyprogesterone
was conducted in China, and demonstrated
uniform azoospermia in subjects receiving both

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TESTOSTERONE PLUS GONADOTROPINRELEASING HORMONE ANTAGONISTS

GnRH agonists (such as Lupron, Abbott

Laboratories, IL, USA) are not effective when
used with testosterone in male hormonal contraception, but the combination of GnRH antagonists and testosterone remains a promising
option. GnRH antagonists can suppress FSH
and LH production within hours of administration, and inhibit gonadotropin secretion more
completely than agonists do. Small trials of male
hormonal contraceptives have been conducted
using the GnRH antagonist Nal-Glu, administered by daily subcutaneous injection, in combination with testosterone. In the first two trials, 14
out of 16 subjects achieved azoospermia after
610 weeks of treatment.51,52 A third randomized trial, however, demonstrated no difference in azoospermia when TE plus Nal-Glu
was compared with TE alone.53 GnRH antagonists could have a useful role in the induction
of azoospermia, as one study demonstrated
that Nal-Glu could induce azoospermia when
administered with TE for 12 weeks, which was
then maintained by TE alone for an additional
20 weeks.54
The GnRH antagonist, cetrorelix, has been
used in a male contraceptive study in which
it was combined with the androgen 19nortestosterone.55 Azoospermia was achieved
by 12 weeks in all six subjects; however, it could

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1,000
Treatment period
Sperm concentration (millions/ml)

medroxyprogesterone acetate and TU, but not

in those receiving TU alone (Figure 2).50 This
combination is therefore an attractive candidate
for larger efficacy studies in Chinese men. One
drawback to the use of medroxyprogesterone
acetate is longer recovery times for spermatogenesis, with a few subjects sperm counts
returning only after extended follow-up of
69 months.13,50
In summary, the contraceptive effect of
most of the progestogens is fairly similar, as
combinations of intramuscular TU or testosterone pellets and levonorgestrel, etonogestrel,
norethindrone or medroxyprogesterone all
result in azoospermia rates of almost 90%. As
a result, many researchers now feel that one of
these combinations is the most likely to result
in a clinically useful contraceptive method;
however, larger-scale phase III studies of efficacy at pregnancy prevention will need to be
carried out with these regimens before they can
be marketed.

100

10

0.1
4

12

16

20

24

28

32

36

40

44

48

Time (weeks)

Figure 2 Mean sperm counts in men treated with 1,000 mg of testosterone

undecanoate every 8 weeks alone (diamonds) or with 150 mg (squares) or
300 mg (triangles) of medroxyprogesterone acetate every 8 weeks (arrows).
All 20 subjects in the testosterone undecanoate plus medroxyprogesterone
acetate groups achieved azoospermia by 20 weeks of treatment. Reproduced
with permission from reference 50 (2004) The Endocrine Society.

not be maintained after the cetrorelix was

discontinued, perhaps because 19-nortestosterone
cannot be aromatized to estrogen, which plays a
role in the feedback suppression of gonadotropin
secretion at the pituitary.
Longer-acting GnRH antagonists have recently
been developed. A depot formulation of the
GnRH antagonist abarelix results in effective
gonadotropin suppression for periods up to
1 month,56 but case reports of allergic reactions
to this agent could limit its clinical utility. The
GnRH antagonist acyline can markedly suppress
gonadotropins for up to 2 weeks after a single
subcutaneous administration without significant
side effects.57 In a small trial, 8 weeks of acyline
combined with TE and oral levonorgestrel did
not demonstrably augment sperm suppression
compared with TE and levonorgestrel alone.58
In addition, orally active GnRH antagonists have
been described in the chemistry literature,59
and are exciting prospects for future contraceptive trials. In conclusion, while theoretically
appealing, GnRH antagonists have been relatively understudied compared with testosterone
and progestogen combinations, and practical
considerations might prevent their incorporation
into future contraceptive regimens.

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GLOSSARY

TRANSDERMAL TESTOSTERONE

CAG REPEATS
A trinucleotide repeat in
the androgen receptor,
additional copies of which
attenuate androgen
signaling

Testosterone patches are useful for the treatment of male hypogonadism, but are not effective for male contraception, presumably because
the serum testosterone levels are insufficient
to completely suppress gonadotropin secretion from the pituitary. For example, one study
combining a 5.4 mg testosterone patch with the
progestin levonorgestrel resulted in azoospermia
in only 2 out of 11 men, and counts below
3 million sperm/ml in 3 others.60 Skin reactions
to the patch are also a problem. In a second testosterone-patch study, which combined testosterone
patches with the progestin desogestrel, only 41%
of the subjects achieved azoospermia, and 24%
of participants withdrew from the study because
of skin irritation due to the patches.61 In a third
study, testosterone patches were combined with
oral levonorgestrel, but less than 50% of subjects
achieved azoospermia.62
Androgen gels have also been tested for
male contraception,63,64 but suppression of
spermatogenesis has been poor in comparison
with injectable testosterone. Newer testosterone
gels, however, hold promise for contraceptive
development as they achieve higher serum
testosterone levels and are associated with less
irritation of the skin than testosterone patches
are.65 These gels are currently being tested in
male contraceptive trials, and in the future
could be combined with a progestogen gel as an
all-gel approach to male contraception.

CYP3A4
A cytochrome P450 enzyme
involved in the metabolism
of testosterone to inactive
compounds

ORAL ANDROGENS

Nonsteroidal, selective androgen-receptor

modulators have been described in the chemistry
literature.66 One such compound suppressed
spermatogenesis in rats by 75% after 10 weeks
of treatment.67 Although further animal testing
will be required before these types of compounds
can be studied in humans, they are particularly
appealing as they might allow for oral administration of the androgen component of future male
contraceptive regimens and could, in theory,
minimize any adverse effects on the prostate. In
addition, it has recently been demonstrated that
the oral administration of testosterone in oil,
when combined with a 5-reductase inhibitor (see
below), can result in therapeutic levels of serum
testosterone.68 Given the preference of most men
for an oral form of contraception, a safe form of
oral testosterone would be an improvement over
existing methods of testosterone delivery for
contraceptive purposes.

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WHY DOESNT HORMONAL

CONTRACEPTION WORK FOR ALL MEN?

The major mystery in the field of male contraceptive research is why some men fail to reduce
sperm production to zero despite suppression
of serum gonadotropins to extremely low levels.
Since there are no apparent differences in the
gonadotropin levels among men who achieve
azoospermia and those who do not, the degree
of gonadotropin suppression itself is unlikely
to be the answer.6971 Alternative explanations
include the hypothesis that non-azoospermic
men might have greater 5-reductase activity
in their testes.72 Such a difference would result
in higher intratesticular dihydrotestosterone
(DHT) counts, which could then maintain
spermatogenesis. In support of this theory, intratesticular DHT is relatively well preserved in men
on a male hormonal contraceptive regimen.73
On the other hand, two studies have demonstrated that the addition of the 5-reductase
inhibitor finasteride did not enhance suppression of spermatogenesis beyond that achieved
by TE alone or TE plus desogestrel, as would be
expected if intratesticular DHT was the cause of
persistent sperm production.74,75
Recent work in LH-receptor knockout mice
implies that low levels of constitutively produced
intratesticular testosterone might allow for low
levels of spermatogenesis to persist even in the
absence of a functional LH signal.76 If this is the
case in humans, compounds that inhibit LHindependent testicular testosterone synthesis
might be useful contraceptive agents. Indeed,
the idea that intratesticular testosterone can
promote spermatogenesis despite suppression
of LH and FSH by a male contraceptive regimen
is supported by a recent study combining TE
with cyproterone acetate, which found that
sperm suppression was decreased when 200 mg
of weekly TE was administered compared with
the group receiving 100 mg of weekly TE.77 One
possible explanation for these results is that
some exogenous TE diffused into the testes and
supported low-level sperm production.
Genetic polymorphisms could explain
the difference between men who achieve
azoospermia and those who do not; however, no
candidate polymorphism has been identified. In
one study, neither the number of CAG REPEATS
in the gene encoding the androgen receptor, nor
polymorphisms in the CYPA gene, appeared to
influence individual responsiveness to hormonal
suppression of spermatogenesis in man.78 A

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second study, however, found that a CAG-repeat

number of greater than 22 was associated with
an increased chance of azoospermia in the
setting of incompletely suppressed gonadotropins.79 Clearly, further investigation will be
needed to understand the innate differences
in the intratesticular environment that allow
some men to continue to produce sperm in the
extremely low-gonadotropin environment of a
male contraceptive regimen.
CONCLUSIONS

Research has demonstrated the feasibility of

the hormonal approach to male contraception.
The administration of exogenous testosterones is
able to suppress human spermatogenesis without
severe side effects in most men. Combinations
of testosterone with progestogens and GnRH
antagonists improve suppression of sperm
production. In particular, ongoing trials with
etonogestrel, norethisterone, and medroxyprogesterone combined with long-acting injections of TU or testosterone pellets might result
in a regimen with sufficient efficacy to allow for
regulatory approval and marketing, hopefully
within the next decade. Once approved, largescale follow-up of men receiving hormonal
contraceptives will be required to ensure
there are no harmful long-term side effects on
reproductive or overall health.

7
8

10

11

12

13

14

15

16

17

KEY POINTS

The administration of exogenous testosterone

and progestogens results in suppression of
sperm production that might allow their use in a
male contraceptive

The tolerability and side-effect profiles of

these regimens are favorable

Such regimens are currently 95% effective at

pregnancy prevention

Improved potency and methods of drug

delivery might allow for the introduction of such a
hormonally based male contraceptive in the next
10 years

18

19

20

21

22

23
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Acknowledgments
JK Amory is supported,
in part, by the National
Institute of Child Health
and Human Development,
a division of the National
Institutes of Health, by
grant 1K23 HD4538610A1, and has research
funding from Schering AG
and GlaxoSmithKline. WJ
Bremner and JK Amory
are also supported by
the National Institute of
Child Health and Human
Development through
cooperative agreements
U54-HD-12629 and U54
HD42454 as part of the
specialized Cooperative
Centers Program in
Reproductive Research
and the Cooperative
Contraceptive Research
Centers Program.

Competing interests
JK Amory declared
competing interests; go to
the article online for details.
The other authors declared
they have no competing
interests.

NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 41

2006 Nature Publishing Group