How Close are We in Achieving Safe, Affordable and Reversible Male Contraceptives?

Abstract

The world population, currently estimated to be over six billions, is expected to double in the next forty years. The projected growth will cause severe over crowding that will have an adverse effect on the ecological health of the planet. A recent survey by the United Nations found that a majority of men in many countries are willing to participate in family planning by taking full control of their fertility. However, the available contraceptives for men have either higher failure rates or they are irreversible. Thus, the contraceptive needs of tens of millions of men go unmet every day resulting in millions of unwanted pregnancies, and hundreds of thousands of abortions. Since the introduction of oral contraceptive (pill) for women over five decades ago, there have been numerous collaborative efforts by scientists and pharmaceutical companies to improve the effectiveness and delivery of contraceptives to women who wish to safely regulate their reproductive physiology. However, the contraceptive options available to men have not changed in several decades and are still limited to the use of condoms and timely withdrawal (coitus interruptus) or under going a minor surgical procedure (vasectomy) that prevents the release of spermatozoa during ejaculation. The first two methods have relatively higher typical-use failure rates, whereas the last approach is largely irreversible and not suitable for younger men. Despite non-stop efforts worldwide, we may still be several years away from providing safe, effective and affordable male contraceptives which will allow both men and women to participate fully in family planning. In this article, we will discuss various contraceptives currently available to regulate male fertility. In addition, we will summarize potentially new contraceptives for men that are at various stages of research and development. Finally, our intention is to discuss details of two safe, reversible and affordable male contraceptive approaches that are inching closure to being approved for use by the masses in India and China, the world's two most populous nations.

Full text

Endocrine, Metabolic & Immune Disorders - Drug Targets, 2010, 10, 00-00 1
1871-5303/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.
How Close are We in a Chieving Safe, Affordable and Reversible Male
Contraceptives?
Daulat R.P. Tulsiani1,* and Aïda Abou-Haila2
1Departments of Obstetrics and Gynecology & Cell and Development Biology, Vanderbilt University School of Medi-
cine, Nashville, Tennessee, 37232-2633, USA
2UFR Biomédicale, Université Paris Descartes, 75270 Paris cedex 06, France
Abstract: The world population, currently estimated to be over six billions, is expected to double in the next forty years.
The projected growth will cause severe over crowding that will have an adverse effect on the ecological health of the
planet. A recent survey by the United Nations found that a majority of men in many countries are willing to participate in
family planning by taking full control of their fertility. However, the available contraceptives for men have either higher
failure rates or they are irreversible. Thus, the contraceptive needs of tens of millions of men go unmet every day resulting
in millions of unwanted pregnancies, and hundreds of thousands of abortions. Since the introduction of oral contraceptive
(pill) for women over five decades ago, there have been numerous collaborative efforts by scientists and pharmaceutical
companies to improve the effectiveness and delivery of contraceptives to women who wish to safely regulate their repro-
ductive physiology. However, the contraceptive options available to men have not changed in several decades and are
still limited to the use of condoms and timely withdrawal (coitus interruptus) or under going a minor surgical procedure
(vasectomy) that prevents the release of spermatozoa during ejaculation. The first two methods have relatively higher
typical-use failure rates, whereas the last approach is largely irreversible and not suitable for younger men. Despite non-
stop efforts worldwide, we may still be several years away from providing safe, effective and affordable male contracep-
tives which will allow both men and women to participate fully in family planning. In this article, we will discuss various
contraceptives currently available to regulate male fertility. In addition, we will summarize potentially new contraceptives
for men that are at various stages of research and development. Finally, our intention is to discuss details of two safe,
reversible and affordable male contraceptive approaches that are inching closure to being approved for use by the masses
in India and China, the world’s two most populous nations.
Keywords: Male contraception; fertilization; immunocontraception; intra vas device; sperm function
INTRODUCTION
The current world population, estimated to be over six
billions, is expected to double in the next forty years [1]. The
projected growth will cause critical over crowding of the
planet that will result in severe competition for the available
resources. The projected growth will also have an adverse
effect on the ecological health of the planet. A recent survey
by the United Nations Population Division suggest that a
majority of young men in many countries are willing to par-
ticipate in family planning by taking full control of their
fertility, a global health issue. However, the contraceptive
needs of tens of millions of men go unmet every day result-
ing in millions of unwanted pregnancies and hundred of
thousands of abortions. For men, the contraceptive options
currently available have not changed in several decades and
are still limited to the use of non-surgical methods, like ab-
stinence, timely withdrawal and use of condoms, or a surgi-
cal method of removing a segment of vas deferens or ligating
it (vasectomy) which prevents the transport of spermatozoa
through vas deferens and their release at the time of ejacula-
tion. The non-surgical approaches have relatively higher
*Address correspondence to these authors at the Departments of Obstetrics
and Gynecology & Cell and Development Biology, Vanderbilt University
School of Medicine, Nashville, Tennessee, 37232-2633, USA;
Tel: ???????????; Fax: ???????????; E-mail: daulat.tulsiani@vanderbilt.edu
failure rates whereas the vasectomy is largely irreversible
and may not be suitable for younger men. Thus, providing a
safe, affordable, and reversible contraception for men has
remained an elusive goal.
Since the introduction of oral contraceptive pill for
women over five decades ago, there have been numerous
collaborative efforts by scientists and pharmaceutical com-
panies to improve the effectiveness and delivery of contra-
ceptives to women who wish to safely regulate their repro-
ductive physiology. The so called, “Contraceptive revolu-
tion” of the past century has helped many women in the
developed nations to practice family planning. As a result of
safely spacing births or limiting the size of the family, the
maternal mortality rate in these countries has fallen dramati-
cally. However, for many women in developing nations, the
contraceptive revolution of the past century has yet to come.
Although women in developing nations have several contra-
ceptive options to avoid pregnancies, many of the available
approaches are too expensive to use them on a regular basis.
The lack of affordable and readily available contraceptives
for men and women in many parts of the world often results
in short birth intervals and high mortality rates for mothers
and their newly-born infants [2]. The risk for young mothers
and their newly-born infants can be significantly reduced if
the couples wait for at least two years before attempting to
expand their families. The so called, “Spacing of Children”
in family planning will be relatively easier to achieve if both

2 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2010, Vol. 10, No. 2 Tulsiani and Abou-Haila
men and women can take full control of their fertility by
using safe and effective contraceptives.
Although efforts have continued over the past several
decades to develop safe and user-friendly reversible contra-
ceptives for men, the contraceptive options currently avail-
able to them are relatively limited compared to the options
available to women. The reasons for this difference have
been discussed in a previous review [3] and will not be
repeated here. In this article, we intend to discuss various
contraceptive options currently available to men. In addition,
we will briefly describe potentially new contraceptive
approaches that are at various stages of research and devel-
opment. Finally, we intend to discuss details of two safe,
reversible, and affordable contraceptive approaches for
men that are inching closer to being reality for use by male
population.
WHY DO WE NEED MALE CONTRACEPTION?
The current estimates are that over one million teenage
girls become pregnant in the United States every year. A
significant number of these pregnancies are unintended. It
should be noted that the teenage pregnancy rate in the United
States is twice as high as in Canada or many European coun-
tries [4]. Furthermore, over 20% of these pregnancies in the
United States end up in abortions. These are alarming num-
bers for any Western country and should not be ignored.
Available statistics also show that over half a million
deaths occur from the pregnancy-related complications
world wide. Many more young women suffer from preg-
nancy-related serious illnesses. Moreover, children born into
impoverish families which fail to take full control of their
fertility, will most likely lack the resources needed to escape
life time poverty. According to a report from Children De-
fence Fund published in the Tennessean news paper [5],
every 33 seconds a baby is born in America into poverty.
Black and Latino children in America are about three times
as likely to be poor as white children. Furthermore, almost
one in every 13 children in America lives in extreme pov-
erty. Also, the infant mortality rates are more than twice as
high for black infants than white infants. These numbers are
likely worst for infants born in the third world countries.
These statistics are alarming and suggest that fertility control
is a global health issue that needs to be addressed as soon as
possible.
It should be noted that in less resourceful populations of
all nations, the lack of friendly user contraceptives for men
and women results in short birth intervals and relatively
higher mortality rates for young mothers. This results in
many orphaned children living in single parent families that
are unable to provide them with decent living and educa-
tional opportunities. Considering the existing gloomy situa-
tion, one may wonder why it is taking so long to develop a
reliable and affordable contraceptive for men so that they can
take full responsibility of their fertility. The lack of visible
progress in the male contraceptive field is a concern because
the world’s population, particularly that of developing na-
tions, continues to grow at an alarming rate.
When the question of male contraception is discussed,
many wonder how many men will use them to regulate their
fertility. Available statistics suggest that many men (~30%)
already use currently available contraceptive approaches
which are not very satisfactory [6]. A recent survey by the
United Nations Population Division found that a majority of
young men in many developing countries want fewer chil-
dren than their parents did. However, the contraceptive op-
tions currently available to them are limited to device-free
(abstinence and timely withdrawal) or barrier (condoms and
vasectomy) approaches. Unfortunately, the approaches
which are reversible (device-free approaches and condoms)
have a higher failure rates whereas the most reliable ap-
proach (vasectomy) is largely irreversible. No new male
contraceptives have been introduced in the past century [3,
7]. Thus, it is reasonable to argue that the development of a
safe, affordable and user-friendly contraceptive option for
men will make a significant difference in the effectiveness of
the planning and managing of smaller families in the United
States and other countries. The development of new male
contraceptives, a challenge for the scientific community,
remains an important component of future successes in slow-
ing the growth of world population.
In spite of the general agreement that men must take full
responsibility in regulating their fertility, the existing male
contraceptives are not enough to meet the urgent need of
growing world population. There are no safe, effective and
affordable contraceptive approaches available to men (see
below). Since most women remain at a high risk of contract-
ing sexually transmitted diseases (STDs), an effective male
contraceptive that can provide simultaneous protection
against pregnancy and infections will be of particular interest
to many women. However, we may still be several years
away from providing such an ideal contraceptive to male
population.
Progress in male contraceptive technology is a crucial
part of controlling population growth. This will require a
serious commitment and resources from governments of all
countries and a serious commitment from both small and
large pharmaceutical companies to invest in the research and
development of contraceptives that will meet the growing
need of a large number of men around the world. Since con-
traceptive failure has a personal consequence for women,
serious concerns and uncertainties over whether women who
are not in a permanent (stable) relationship will actually trust
men who claim to be on contraception, have resulted in
patchy investments from pharmaceutical companies. Many
drug companies are also reluctant to invest in the research
and development of male contraceptive products intended for
healthy men who will use them for several decades, raising
the possibility of their unintended side effects on their health,
including the loss of libido.
Despite many hurdles, biomedical researchers around the
globe are making tremendous progress. Thanks to their dedi-
cation, we are inching closure to providing safe, reversible,
and affordable male contraceptives to masses in India and
China, the world’s two most populous countries. We are
hopeful that world wide collaborations will soon begin
to address the studies necessary for the approval of these
contraceptive approaches for men outside India and China.

Male contraception Endocrine, Metabolic & Immune Disorders - Drug Targets, 2010, Vol. 10, No. 2 3
PHYSIOLOGICAL BASIS OF MALE CONTRACEP-
TION
Many details of biological and physiological basis of
male fertility have been discussed in two previous review
articles [3, 7] and will not be repeated here. We will, how-
ever, highlight main features of the male reproductive system
and how it functions. The brief discussion is necessary to
understand what needs to be done to develop male contra-
ceptives. In a sexually mature man, the two testicles or the
testes, produce millions of tiny (microscopic) spermatozoa.
The germ cells are formed throughout post-pubertal male
reproductive life from spermatogonial stem cells in the testes
by a highly orchestrated process referred to as spermato-
genesis. The entire process, described in earlier publications
[8-10], results in the production of hydrodynamically shaped
spermatozoa with a head containing nucleus and acrosome
and flagellum with mid-piece and principal piece. The proc-
ess of sperm formation depends on the specific environment
provided by the testicular somatic cells (Sertoli cells and
Leydig cells) and requires endocrine and paracrine regulation
as well as direct cell-cell interactions [8-10].
Along each testicle, are epididymis and vas deferens (vas)
that make up the network of male reproductive system.
The epididymis is a set of two coiled tubes (one from each
testicle) where testicular spermatozoa undergo many
biological changes, collectively called sperm maturation. As
a result of the multiple changes in the epididymis, spermato-
zoa gain forward motility and become fertilization competent
cells [11-14]. Each epididymis is connected to the vas, a pair
of muscular tubes that transport sperm-containing fluid to
uretha, and semen out of the body through the penis (see Fig
1 in [3]).
The testes, along with epididymis, hang in a specialized
pouch-like structure, the scrotum, outside the pelvis. The
pouch has five features that keep the testes somewhat cooler
than the core body temperature. These features are the: 1)
dartos muscle; 2) cremaster muscles; 3) counter current heat
exchange system; 4) absence of fatty skin layer; and 5)
abundant sweat glands. These five features act in a coordi-
nated manner that enable the testes present outside the body
cavity, to remain 1-2°C cooler than the core body tempera-
ture [10, 15]. Warming the testes by even 1°C can cause a
significant drop in sperm production and their motility, two
important factors that regulate male fertility [3, 16-18]. This
relationship between temperature on the sperm production
and their motility has been exploited to develop fertility
control in men. Many details of the published studies have
been described in earlier article [3] and will not be repeated
here.
It should be noted that the scrotum changes in size to
keep the temperature of the testes 1-2°C cooler than the body
temperature. When the body temperature is warm, scrotum
becomes larger and hangs away from the body cavity. How-
ever, when body temperature is cool, the scrotum shrinks and
becomes tighter to hold the body heat. The temperature-
sensitive manipulations of the scrotum keep the sperm pro-
duction at a constant level.
In addition to the testes, epididymides, and vas, there are
two accessory glands namely the seminal vesicles and pros-
tate gland. These glands provide fluids that lubricate the duct
system. The seminal vesicles are sac-like structures attached
to the vas where as the prostate gland surround the ejacula-
tory ducts at the base of urethra, just below the bladder (see
Fig. 1 in [3]). The prostate, present only in males, is a part of
every man’s reproductive system. It requires male sex hor-
mone, testosterone, to function properly, helping to regulate
bladder control and normal sexual function.
The urethra is the tube that transports semen (seminal
plasma containing spermatozoa) out of the body through the
penis, a spongy organ which can expand and contract de-
pending on man’s state of sexual arousal. The male repro-
ductive system works together to produce and release sper-
matozoa into the female reproductive tract during coitus. The
ejaculated spermatozoa undergo chemical and functional
changes during residence in the female reproductive tract,
collectively referred to as capacitation [19-22], a multifac-
eted process that produces hyperactivated spermatozoa capa-
ble of binding, by their anterior head surface, to the egg’s
extracellular coat, the zona pellucida [22-26]. Accumulated
data suggest that sperm-egg interaction is a species-specific
event [19] which is mediated by sperm surface receptors on
capacitated spermatozoa and their complimentary ligands on
the zona pellucida [23-26]. Finally, the bound spermatozoa
undergo signal transduction cascade that result in the exocy-
tosis of acrosomal contents [22]. The hydrolytic action of
acrosomal glycohydrolases and proteases, released at the site
of sperm-zona (egg) binding, along with the enhanced thrust
generated by the hyperactivated beat pattern of the bound
spermatozoa, are important factors that regulate penetration
of the zona pellucida, and fertilization of the egg [22, 27,
28].
The complexity of the science of male reproductive sys-
tem has kept the male contraceptive field challenging. First,
the blood-testis barrier that exists in men inhibits/prevents
the potential anti-fertility agent(s) from entering seminifer-
ous tubules in the testes, the site where sperm cells are
formed from spermatogonia by a complicated process called
spermatogenesis [8-10]. Even if the potential anti-fertility
agent(s) can be delivered by manipulating the dose and de-
livery system, there remains the possibility that the delivered
drug may have an adverse effect on spermatogonia, the male
germ cells [9, 29], causing permanent infertility in the treated
men. Second, the effect of many potential drugs may not be
tissue specific (testis-specific), and could cause unintended
effects on other tissues that will have an adverse effects on
men’s health. Finally, the cost-effectiveness (affordability) is
an important consideration. Combined, these hurdles have
kept many pharmaceutical companies on the sidelines and
prevented development of safe and affordable contraceptives
for male population.
MALE CONTRACEPTIVES: CURRENT AND
FUTURE APPROACHES
The purpose of male contraception is to either prevent
sperm from reaching the egg or prevent sperm-egg interac-
tion that leads to fertilization. This can be achieved by 1)
suppressing/preventing sperm production in the testes [8-10,
29]; 2) prevent sperm from reaching the site of fertilization
[23-26]; and 3) interfere with sperm function(s) necessary
for normal fertilization [22, 27, 28]. From the above discus-

4 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2010, Vol. 10, No. 2 Tulsiani and Abou-Haila
sion, it is apparent that the male reproductive system pro-
vides numerous target sites for the development of reversible
contraceptives for men. However, many details that regulate
sperm production in the testes, maturation in the epididymis,
capacitation in the female reproductive tract, and sperm-egg
binding leading to fertilization are far from clearly under-
stood, making it difficult to target a particular event for the
development of a safe, reversible, and affordable contracep-
tive for men.
Thus the contraceptive options currently available to men
have not changed in several decades and are still based on
approaches that prevent sperm from reaching the egg using
either device-free traditional methods (abstinence and with-
drawal) or methods which use barriers (condoms and vasec-
tomy). No new contraceptives for men have been introduced
in the past century. In this section, we will highlight the
advantages and disadvantages of currently available contra-
ceptives before discussing new contraceptives that may be
on the horizon in near future.
1. Device-Free Approaches
The traditional methods are cost-effective and theoreti-
cally effective in preventing pregnancies. The device-free
traditional approaches have been in practice for centuries;
however, these approaches have high failure rates (~25%)
and limited acceptability. Abstinence and timely withdrawal
fall into this category of male contraception.
1a) Abstinence
Abstinence may mean different things to different
groups. For some, it means not to engage in any form of
sexual intercourse with a partner. This form of abstinence is
100% effective in preventing pregnancies and STDs. How-
ever, to some it means limiting the sexual activity to, “safe
days” of the estrous cycle of the female partner. In the de-
vice-free and cost-free approach, the sexual intercourse can
be carried out only on the safe days of the cycle and is rea-
sonably safe method as long as the female partner has a
regular cycles (regular periods). The no sex rule has to be
followed several days before and after ovulation (mid-point
of the normal cycle of 28 days). The approach is practiced by
millions of couples throughout the world as a method of
family planning. The approach, however, has about 25%
failure rates which limits its acceptability by a large popula-
tion.
1b) Withdrawal
This is another device-free and cost-free traditional con-
traception for men who withdraw from regular intercourse
(coitus interruptus) in such a way that the ejaculation is
completed at an extra-vaginal site(s). The traditional ap-
proach is also used by tens of millions of couples throughout
the world. It is a reasonably reliable method of family plan-
ning for experienced couples. However, the approach has a
higher failure rate for new and inexperienced men and
should never be attempted by teenagers or young couples.
2) Barrier Methods
The so called barrier methods (condoms and vasectomy)
present barrier and prevent sperm from being released in the
female genital tract during coitus. Recent numbers reported
in the Male Contraceptive.Org bulletin suggest that a signifi-
cant number of sexually active couples (> 30%) use barrier
methods for their primary birth control needs.
2a) Condoms
The modern condom, made of rubber, latex or polyure-
thane, is a balloon-like device that is put on man’s erect
penis before and during sexual intercourse. The device pro-
vides a barrier and prevents ejaculated semen from entering
the reproductive tract of the partner. When condoms are not
defective and are used correctly, they provide protection
from unwanted pregnancies as well as STDs and low-risk
and high-risk papilloma viruses [30, 31]. Despite opposition
from the Roman Catholic Church, condoms have been in use
for centuries. Condoms provide a cost-effective reversible
contraception for men. Since no medication is required, men
do not need to be examined by a physician for prescription.
They can be bought at the counter in most countries and
provide the user-controlled and reversible contraception for
men with fewer complications. Condoms, though used by
millions of men world-wide as the only source of birth con-
trol, have relatively higher typical-use failure rates. They are
also known to interfere with sexual spontaneity which limits
their popularity among couples in a stable relationship.
India was the first country to introduce the Government
sponsored birth control program in the 60s throughout the
nation. Free condoms were distributed to men to slow down
the population growth in the country. At present, condoms
are made available in India and many other countries to
prevent the spread of STDs as well as unwanted pregnancies.
In the USA, New York City was the first major city to start
an internet-based “Free Condoms Initiative” and provide
community and social organizations with free condoms to
prevent STDs. Since the inception of the program in 2005,
the condom distribution in the New York City has grown 5-
fold. The programs introduced in India and New York City
will likely serve as model programs for other countries and
cities to provide free condoms in poor communities and
prevent unwanted pregnancies as well as spread of STDs.
2b) Vasectomy
The male contraceptive method, used by millions of men
for regulating their fertility, is a minor surgical procedure
that involves removal of vas or occlusion of vas, the
tube which transports sperm to the penis. In the traditional
vasectomy, the physician makes one or two incisions in the
scrotum under local anaesthesia to expose vas tube which is
cut and occluded [32]. In the vast majority of the vasectomy
patients, the procedure is simple with no known side effects
on other parts of the body including the testes and pe-
nis. Also, the surgery has no known changes on the level of
testosterone hormone, semen volume, sexual function or
libido.
Vasectomy is highly effective in regulating male fertility
once spermatozoa have cleared from the distal vas deferens.
Most patients (95% of men) reach this state in 3 months after
vasectomy or after patients had at least 20 ejaculations. In
most cases, there are no known reports of post-surgical com-
plications. However, a small number of patients have re-
ported post-vasectomy complications including bleeding,

Male contraception Endocrine, Metabolic & Immune Disorders - Drug Targets, 2010, Vol. 10, No. 2 5
hematoma, swelling of the testes, minor pain, and allergy to
local anaesthesia.
A modification to the traditional vasectomy was intro-
duced in China in 1974 which eliminates the use of scalpel
[33]. The no-scalpel vasectomy is less invasive and mini-
mizes skin incision and reduces immediate side-effects such
as bleeding and possible infection. The procedure, like the
traditional vasectomy, is done under local anaesthesia. In the
no-scalpel vasectomy, the surgeon uses a curved sharp he-
mostat to puncture the skin of scrotum, and exposes the vas
deferens. The exposed vas tubes are either tide or sealed, and
placed in the scrotum. The procedure in most cases requires
no stitches to close the tiny skin opening. During the surgery,
there is very little bleeding and fewer chances of any com-
plications compared to the traditional vasectomy. The patient
remains awake during the procedure, and is allowed to leave
the surgeon's office after brief rest and relaxation. The no-
scalpel procedure has additional advantage in that the pa-
tients can resume sexual activity sooner compared to the
patients who have undergone the traditional vasectomy. The
procedure being less complicated and less painful has a
higher acceptance rate; however, the procedure, like the
traditional vasectomy, does not assure reversibility.
No needle, no-scalpel vasectomy is yet another modifica-
tion to the traditional, and no-scalpel vasectomy. The proce-
dure uses a jet injection to spray an anaesthetic solution
through the skin and around the vas prior to the minor proce-
dure. The entire procedure uses two instruments; a ring for-
ceps to encircle and secure the vas without penetrating the
skin of scrotum. A sharp lipped dissecting forceps is then
used to puncture the skin and make a small opening in the
skin of scrotum, and vas sheath; the vas tube is lifted and
occluded. Unlike the traditional and no-scalpel vasectomy,
no stitches are needed in the modified approach and no
stitches are needed to close the small opening. Thus the
procedure is less invasive than the no-scalpel vasectomy.
However, the modified approach does not improve the
chances of reversibility.
How do the various vasectomies work as a male contra-
ceptive? As stated above, sperm cells are made in the testes
by a complex process called spermatogenesis [8-10]. The
testicular spermatozoa undergo multiple biochemical
changes in the epididymis and are transported through two
vas tubes (vas deferentia) suspended in the testicular and
epididymal fluids. During sexual climax, millions of sper-
matozoa are mixed with secretions of accessory glands to
form the semen (sperm in the seminal plasma) which is
ejaculated in the female genital tract during the completion
of sexual intercourse. If one of the millions of ejaculated
sperm cells fertilizes the egg, the female partner becomes
pregnant. During vasectomy, a segment of the vas tube is
either removed or the tubes are occluded. The procedure
prevents the transport of spermatozoa through the vas tubes.
Without sperm in the semen, a man can no longer make his
female partner pregnant. It should, however, be noted that
after the procedure, men have normal erections and during
ejaculation, the volume of semen is not significantly differ-
ent than before the procedure; however, the semen of vasec-
tomized men has no spermatozoa or very few non-motile
spermatozoa.
Although the various vasectomy procedures described
above can be reversed in some cases by a delicate microsur-
gery performed by a highly trained physician, the pregnancy
rates after the reversal surgery are low and largely depend on
the skill of the physician and the time elapsed since the va-
sectomy [34-38]. Thus, it is reasonable to conclude that the
various vasectomy procedures (see above) in typical circum-
stances are mostly irreversible and may not be suitable for
younger men. However, the procedure is widely used by men
who have completed their families and are not concerned of
getting STDs from their partners. Newer and more cost-
effective techniques are being introduced for reversal of
vasectomy [39, 40]. We are hopeful that in the near future,
these cost-effective techniques will be used efficiently to
make vasectomy approaches reversible. This will make the
procedure more acceptable to younger men who have not yet
completed their families but will like to take full control of
their fertility.
FUTURE PROSPECTS OF MALE CONTRACEPTION
Despite world wide efforts over the past several decades
to develop safe, reversible and affordable contraceptives for
men, the contraceptive options currently available to men
(see above) have not changed in several decades. Thus, pro-
viding effective and readily available contraception for men
has remained an unfulfilled goal. However, thanks to the
dedicated efforts by biomedical researchers and clinicians
around the globe, many new approaches to regulate male
fertility appear to be within our reach. We will list all poten-
tially new approaches that are at various stages of research
and development, and give a brief rationale as to how they
will function as effective contraceptives for men. In addition,
we intend to present details of two approaches that are show-
ing promising results in clinical trials in the world's two most
populous nations. When approved for use by masses of male
population in India and China, the approaches are expected
to provide safe, affordable, and reversible contraception for
millions of men.
As stated above, the male reproductive system provides
numerous events that can be targeted for the regulation of
male fertility. However, since the mechanism(s) of various
target events are still far from clear, it has been difficult to
target any particular event or site for the development of
male contraceptive(s). Furthermore, identifying the potential
target site(s) for the development of male contraceptive is an
expensive and time consuming process. Even after the target
site is validated, the painstaking process of identifying safe
and effective reagents (drugs) to regulate male fertility re-
quires coordinated efforts of the basic and clinical research-
ers as well as participation of small and large pharmaceutical
companies. Thanks to the dedicated efforts by researchers
around the globe, we are inching closure to providing male
contraceptives to masses. The diverse approaches that are at
various stages of research and development include: 1) Sup-
pressing/arresting sperm production in the testes by adminis-
tering hormones or non-hormonal reagents; 2) block-
ing/inhibiting sperm function(s) necessary for normal fertili-
zation; 3) immunization of males with well-characterized
male antigens (immunocontraception). The antibodies are
expected to prevent sperm from fertilizing the egg; and 4)
interfere with the delivery of spermatozoa at the site of fer-

6 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2010, Vol. 10, No. 2 Tulsiani and Abou-Haila
tilization. In addition, attempts are being made to a) arrest
sperm formation by activating testis-specific genes/gene
products [41].; and b) interfere with sperm maturation in the
epididymis in such a way that will block its function(s) [42].
Many details of various approaches are described elsewhere
[3] and will not be repeated here. We will, however, briefly
explain various possibilities for the development of reversi-
ble contraception for men.
1. Suppressing/Arresting Spermatogenesis
Based on the current knowledge of the development of
spermatozoa in the testes, investigators are working on sev-
eral approaches to develop new and readily available hormo-
nal-based and non-hormonal contraceptives for men.
A. Hormonal-Based Approaches
As described in our previous article [3], sperm produc-
tion in the testes depends on pituitary gonadotropins, such as
luteinizing hormone (LH) and follicular stimulating hormone
(FSH). Thus, the hormonal approach, based on administering
anti-gonadotropin agents, such as androgens, estrogens,
progestin or gonadotropin releasing hormone (GnRH), will
inhibit the production of LH and FSH and interfere with
sperm formation [43, 44]. The adverse effects of the anti-
gonadotropin hormones on sperm production can be reversed
by stopping the hormone treatment. Two approaches (clini-
cal trials) that have been tried on volunteers include a com-
bination of progestin and androgen, or a high dose of testos-
terone. The progestin is supplemented with the androgen
because if administered alone, the hormone can cause loss of
libido due to its effect on testosterone deprivation [44].
Various combinations of the anti-gonadotropin hormones
have completed Phase II clinical trials with proven reversi-
bility in men [44]. Thus it appears that a hormone-based
male contraceptive is within our reach. However, the ap-
proach has two important hurdles. First, the ethnic difference
between Asian men (> 90% responsive) compared to Cauca-
sian men (~ 60% of Europeans, Americans, and Australian
men are responsive). Second, it is not clear if the approach
will be cost-effective (affordable) to masses. These are seri-
ous hurdles which make it difficult to predict the future of
the hormone-based contraceptives for men.
Another approach to suppress/inhibit spermatogenesis is
to use selective androgen receptor modulators [45], the non-
steroidal molecules that mimic steroids and bind to androgen
receptor without unintended side effects of steroids. The
binding of modulators to androgen receptor suppresses LH
production and inhibits spermatogenesis. This approach is
still in the early stages of basic research and the actual prod-
uct for safety and clinical trials may not be available for
several years.
B. Non-Hormonal Approaches
Many natural and synthetic compounds have the ability
to either inhibit/suppress spermatogenesis or interfere with
sperm function necessary for normal fertilization. Various
natural compounds that have an adverse effects on sperm
production include Gossypol, a polyphenolic yellow pigment
found in cotton seeds; Tripterygium family vines which
grow in China contain several compounds with known ef-
fects on male fertility [46, 47]; and chloroform extracts of
Papaya seeds [48-50]. Many details of the natural products
and how they interfere in spermatogenesis have been dis-
cussed in greater details in an earlier article [3] and will not
be repeated here. Suffice it to say that the natural compounds
are still at the experimental stages and the actual product to
regulate fertility in men may not be available for many years.
In addition to the natural products discussed above, two
synthetic chemicals have ability to interfere with spermato-
genesis. Adjudin (AF-2364) [51, 52] and N-
butyldeoxynojirimycin [53, 54] are non-toxic agents which
when administered to rodents adversely affected sperm pro-
duction. The adverse effect on spermatogenesis was reversed
after the administration of these compounds was stopped for
several weeks [52, 54]. These compounds or their analogues,
though not tested in men, are promising agents which can be
used in form of a "male contraceptive pill". However, many
years of safety and clinical trials have to be done before
these compounds or their analogues can be used as safe and
reliable contraceptives.
2. Inhibiting/Blocking Sperm Functions Necessary for In
Vivo Fertilization
As stated above and in a recent article [22], capacitation
is a multifaceted change in the biology and physiology of
spermatozoa, including hyperactive sperm motility [19, 55].
The process is regulated by multiple signal transduction
pathways [22]. However, accumulated evidence, discussed in
previous articles [22, 55], suggest that elevation in intra-
sperm Ca2+ is responsible for hyperactivated sperm motility,
a progressive moving pattern of spermatozoa essential for
fertilization. The swimming pattern is characterized by high-
amplitude waves and highly asymmetric flagellar beating
[19], a specific form of flagellar movement which provides
propulsion that helps the bound sperm to exert force neces-
sary to penetrate the zona pellucida and fertilize the egg [22,
27, 56]. Thus it is important to understand the mechanism(s)
of Ca2+ influx and various sperm molecules that regulate the
entry of the cation. This will allow investigators to identify
antagonists (drugs) that can prevent/inhibit the influx of Ca2+
and alter sperm function (hyperactivated motility etc) neces-
sary for fertilization
Although the mechanism that elevates the intra-sperm
Ca2+ remains evasive, it is generally believed that Ca2+ chan-
nels regulate the Ca2+ entry and sperm motility. Several Ca2+
channels have been identified in sperm cells [57-62]; some
of these channels are thought to regulate the intra-sperm Ca2+
levels and hyperactivated sperm motility. CatSpers, the pro-
totype of new ion channel proteins, are receiving greater
attention. The ion channels are expressed in the flagellum of
the male germ cells, and are thought to regulate sperm func-
tion [60-62]. Indeed, the disruption of sperm-specific volt-
age-gated cation channel, CatSper2, had no effect on sperm
production, their forward motility or capacitation-associated
protein tyrosine phosphorylation; however, the CatSper2-
null male mice were completely infertile [59, 63, 64].
The defect in the CatSper2-null sperm cells has been
identified as failure of the cells to acquire hyperactivated
motility. Without the hyperactivated motility, spermatozoa
are incapable of generating the physical force needed to

Male contraception Endocrine, Metabolic & Immune Disorders - Drug Targets, 2010, Vol. 10, No. 2 7
penetrate the egg’s extracellular matrix, the zona pellucida
[23-27]. Since other investigators have attributed infertility
in a human family to a mutation in sperm CatSper2 gene
[65], this Ca2+ channel is considered an attractive target for
sperm function-directed male contraception. However, an-
tagonists (drugs) to block the biological activity of the chan-
nel have yet to be identified before they can undergo safety
and clinical trials.
3. Immunocontraceptive Approaches
It should be noted that a number of women and men are
naturally infertile due to the presence of anti-sperm antibod-
ies in their blood. Although the reason(s) for the infertility
remains elusive, it is generally believed that the antibodies
bind to the male and/or female gametes (spermatozoa and/or
egg) and prevent fertilization [66]. Investigators are hopeful
that when a complete mapping of sperm molecules becomes
available, it will likely provide useful insights about the
identities of antibodies against sperm molecules and the
likely cause of infertility in certain men and women. Several
putative sperm surface molecules thought to participate in
sperm-egg interaction leading to fertilization [26, 67], are
still in basic science stage. After these antigens have been
validated, they will be used to vaccinate non-human and
human primates that may lead to male contraceptive vaccine.
Scientists around the globe are collaborating to develop a
male contraceptive vaccine against "Eppin" a male-specific
antigen present in the testes and epididymides. Many de-
tails of immunization with the Eppin have been described in
our previous article [3, 68]. Suffice it to say that results from
these studies are partially effective. Additional studies are
needed before Eppin or other male antigen can be used for a
safe, cost-effective, and reversible immunocontraception for
men.
4. Vas-Based Approaches to Regulate Male Fertility
As stated above, vasectomy can be reversed in some
cases by micro-surgery performed by a highly skilled physi-
cian; however, the procedure in typical circumstances is
largely irreversible. Scientists are engaged in developing the
vas-based reversible approaches to regulate male fertility.
These approaches will be largely reversible and can be used
by young men who have not yet completed their family.
Many details of various approaches have been discussed in
an earlier article [3] and will not be repeated here. However,
two approaches have undergone multiple clinical trials in
India and China, and are inching closure to being approved
for use by masses in these countries.
Reversible Inhibition of Sperm Under Guidance
(RISUG) approach is similar to reversible no-scalpel vasec-
tomy (see above) except the method uses a non-toxic chemi-
cal. The chemical (Styrene maleic anhydride), dissolved in
dimethyl sulfoxide (DMSO), is injected in the lumen of each
vas tube with or without exposing them. The soluble chemi-
cal first coats the inner walls of the vas tube and than polym-
erizes (solidifies) and causes the vas tubes to be partially or
fully blocked that prevents the transport of spermatozoa
through the tube. Also, the chemical being poly-electrolytic
in nature, kills sperm cells when they come in contact with
the bioactive polymer by completely disintegration of the
sperm plasma membrane [69, 70]. The RISUG approach can
be reversed by the injection of DMSO or a solution of so-
dium bicarbonate in the lumen of the vas tubes. These com-
pounds solubilize the polymer and flushes it out of the tubes
[3, 71], allowing sperm cells to transport through the tubes.
Thus the approach is similar to no-scalpel vasectomy except
it is reversible. Furthermore, the approach has another ad-
vantage over vasectomy since it is effective immediately
after the chemical is injected into the vas tubes; this allows
the patient to resume sexual activity immediately after the
procedure. In contrast, vasectomy may take 3 months before
the patient becomes fully infertile.
The chemical is inexpensive and can provide safe, af-
fordable, and reversible male contraception for masses. The
approach, supported by the Government of India, has suc-
cessfully completed Phase I [72] and Phase II [73] clinical
trials, and is undergoing phase III clinical trials at six inde-
pendent centres in India. Data from these trials have not yet
been made public; if they are in line with the expectations,
we will soon have reversible male contraception for masses
in India. It is our understanding that serious negotiations are
underway to continue work on RISUG in the USA for its use
as a male contraceptive out of India. When this happens,
RISUG approach to regulate male fertility will be available
throughout the world.
Another vas-based male contraceptive approach undergo-
ing clinical trials in China, uses Intra-vas device (IVD) to
prevent/block the transport of spermatozoa. A preformed
urethane tube (less than one inch long), filled with a medical-
grade nylon mesh, is inserted in each vas tube after a minor
surgical procedure. The nylon mesh acts as sieve to capture
spermatozoa and allows testicular / epididymal fluid to pass
through the vas. The IVD has successfully undergone Phase
I and Phase II clinical trials [74]. The new trials, sponsored
by the State of Family Planning of China, include insertion
of the IVD in 1,500 men and follow-up at 3 months, 1 year
and 2 years. Data from these trials show that the approach is
less effective (94% effective) compared to the no-scalpel
vasectomy (98%effective). However, the approach is re-
versible and causes fewer complications than the vasectomy.
Thus, it is possible that we may have to give up efficacy for
safety and reversibility. It is also possible that few minor
changes in the device may improve its efficacy without giv-
ing up safety.
In conclusion, the article summarizes current status of
research and development on several promising possibilities
for regulating male fertility. We conclude that developing
safe, affordable, and reversible contraception for men is
inching closure to being reality. It should, however, be noted
that contraceptive failure has a greater personal conse-
quences for women than for men. Thus, their trust of male
partners claiming to be on a contraceptive is an important
factor which will determine the future successes of male
contraceptive products.
ACKNOWLEDGMENTS
We gratefully acknowledge the male contraceptive orga-
nization (Male Contraceptive.Org) for some of the informa-
tion included in this report. We are grateful to Lynne Black
for help in preparation of this article. Our sincere apologies

8 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2010, Vol. 10, No. 2 Tulsiani and Abou-Haila
to investigators whose relevant work may not have been
cited in this article.
ABBREVIATIONS
LH = Luteinizing Hormone
FSH = Follicle Stimulating Hormone
GnRH = Gonadotropin Releasing Hormone
DMSO = dimethyl sulfoxide
IVD = Intra Vas Device
RISUG = Reversible Inhibition of Sperm
Under Guidance
STDs = Sexually Transmitted Diseases
REFERENCES
[1] U.S. Consus Bureau-World Pop clock Projection; the world at
UN.org.
[2] WHO; UNICEF; the World Bank (2007). Maternal mortality in
2005. Geneva, Switzerland: World Health Organization.
[3] Tulsiani, D.R.P. and Abou-Haila, A. (2008) Male contraception: an
overview of the potential target events. Endocr. Metab. Immune
Disord. Drug Targets, 8, 122-131.
[4] Trussel, T. and Wynn, L.L. (2008) Reducing unintended pregnancy
in the United States. Contraception, 77, 1-5.
[5] The state of American children. Tennessean, February 8, 2009:
17A; www.childrendefense.org/stateofAmerican children.
[6] Mosher, W.D.; Martinez, A.; Chandra, A.; Abma, J.C. and Wilson,
S.L. Use of contraception and use of family planning services in
the United States: 1982-2002 (number 350, December 10 ed.): U.S.
Department of Health and Human Services - Centers for Disease
control and Prevention – National Center for health Statistics – Di-
vision of vital statistics.
[7] Blithe, D. (2008) Male contraception: what is on the horizon ?
Contraception, 78, Suppl. 4: S23-7.
[8] de Kretser, D.M.; Kerr, J.B. In: The Physiology of Reproduction;
Knobil, Neill, Eds.; Raven Press: New York, 1994; pp. 1177-1290.
[9] Kierszenbaum, A.L. (1994) Mammalian spermatogenesis in vivo
and in vitro: a partnership of spermatogenic and somatic cell linea-
ges. Endocr. Rev. 15, 116-134.
[10] Abou-Haila, A. and Tulsiani, D.R.P. (2000) Mammalian sperm
acrosome: formation, contents and function. Archiv. Biochem. Bio-
phys., 379, 173-182.
[11] Orgebin-Crist, M.C. in Acta Medica – Morphological Basis of
Human Reproduction Function, de Kretser, Spera, Eds.; New York,
1987; pp. 115-174.
[12] Dacheux, J.L.; Gatti, J.L.; Dacheux, F. (2003) Contribution of
epididymal secretory proteins for spermatozoa maturation. Mi-
crosc. Res. Tech., 61, 7-17.
[13] Toshimori, K. (2003) Biology of spermatozoa maturation: an
overview with an introduction to this issue. Microsc. Res. Tech.,
61, 1-6.
[14] Tulsiani, D.R.P. (2006) Glycan-modifying enzymes in luminal
fluid of the mammalian epididymis: an overview of their potential
role in sperm maturation. Mol. Cell. Endocrinol., 250, 58-65.
[15] Morgentaler, A.; Stahl, B.C. and Yin, Y. (1999) Testis and tem-
perature: an historical, clinical, and research perspective. J. An-
drol., 20, 189-195.
[16] Rock, J. and Robinson, D. (1965) Effect of induced intrascrotal
hyperthermia on testicular function in man. Am. J. Obstet. Gyne-
col., 93, 793-801.
[17] Mieusset, R.; Bujan, L.; Mansat, A. and Pontonnier, F. and Grand-
jean, H. (1987) Hyperthermia and human spermatogenesis: en-
hancement of the inhibitory effect obtained by artificial cryp-
torchidism. Int. J. Androl., 10, 571-580.
[18] Mieusset, R. and Bujan, L. (1994) The potential of mild testicular
heating as a safe, effective and reversible contraceptive method for
men. Int. J. Androl., 17, 186-191.
[19] Yanagimachi, R. In: The Physiology of Reproduction; Knobil,
Neill, Eds.; Raven Press: New York, 1994; pp. 189-317.
[20] Yanagimachi, R. and Chang, M. (1963) Fertilization of hamster
eggs in vitro. Nature, 200, 281-282.
[21] Suarez, S.S. (1987) Sperm transport and motility in the mouse
oviduct: observations in situ. Biol. Reprod., 36, 203-210.
[22] Abou-Haila, A. and Tulsiani, D.R.P. (2009) Signal transduction
pathways that regulate sperm capacitation and the acrosome reac-
tion. Arch. Biochem. Biophys., 485, 72-81.
[23] Wassarman, P.M. (1995) Mammalian fertilization: egg and sperm
(glyco)proteins that support gamete adhesion. Am. J. Reprod. Im-
munol., 33, 253-258.
[24] Shur, B.D. (1993) Glycosyltransferases as cell adhesion molecules.
Curr. Opin. Cell Biol., 5, 854-863.
[25] Myles, D.G. (1993) Molecular mechanisms of sperm-egg mem-
brane binding and fusion in mammals. Dev. Biol., 158, 35-45.
[26] Tulsiani, D.R.P.; Yoshida-Komiya, H. and Araki, Y. (1997) Mam-
malian fertilization: a carbohydrate-mediated event. Biol. Reprod.,
57, 487-494.
[27] Katz, D. and Drobnis, E. In: Fertilization in Mammals; Bavister,
Cummins, Ers, Eds.; Norwell: Serono symposium, 1990;
[28] Tulsiani, D.R.P.; Abou-Haila, A.; Loeser, C.R. and Pereira, B.M.J.
(1998) The biological and functional significance of the sperm
acrosome and acrosomal enzymes in mammalian fertilization. Exp.
Cell Res., 240, 151-164.
[29] Eddy, E.M.; O’Brien, D. In: The Physiology of Reproduction;
Knobil, Neill, Eds.; Raven Press: New York, 1994; pp. 29-77.
[30] Steiner, M.J. and Cates, W.Jr. (2006) Condoms and sexually-
transmitted infections. N. Engl. J. Med., 354, 2642-2643.
[31] Winer, R.L. ; Hughes, J.P.; Feng, O.; O’Reilly, S.; Kiviat, N.B.;
Holmes, K.K. and Koutsky, L.A. (2006) Condom use and the risk
of genital human papillomavirus infection in young women. N.
Engl. J. Med., 354, 2645-2654.
[32] Davis, J. and Pollack, A.E. In: Fertility Control; Carson, Derman,
Tyrer, Eds.; Golden Publishers: London, 1994;
[33] Li, S.; Goldstein, M. and Huber, D. (1991) The non-scalpel vasec-
tomy. J. Urol., 145, 341-344.
[34] Schwingl, P.J. and Guess, H.A. (2000) Safety and effectiveness of
vasectomy. Fertil. Steril., 73, 923-936.
[35] Ansbacher, R. (1971) Sperm-agglutinating and sperm-
immobilizing antibodies in vasectomized men. Fertil. Steril., 22,
629-632.
[36] Sokal, D.C. and Labrecque, M. (2009) Effectiveness of vasectomy
techniques. Urol. Clin. North Am., 36, 317-329.
[37] Silber, S.J. (1978) Vasectomy and vasectomy reversal. Fertil.
Steril., 29, 125-140.
[38] Sharlip, I.D. (1993) What is the best pregnancy rate that may be
expected from vasectomy reversal ? J. Urol., 149, 1469-1471.
[39] Robb, P. and Sandlow, J.I. (2009) Cost-effectiveness of vasectomy
reversal. Urol. Clin. North Am., 36, 391-396.
[40] Lipshultz, L.I.; Rumohr, J.A. and Bennett, R.C. (2009) Techniques
for vasectomy reversal. Urol. Clin. North Am., 36, 375-382.
[41] Yang, J.; Medvedev, S.; Yu, J.; Schultz, R.M. and Hecht, N.B.
(2006) Detection of the DNA/RNA-binding protein MSY2 leads to
post-meiotic arrest. Mol. Cell. Endocrinol., 250, 20-24.
[42] Au, S.C.L.; Hinton, B.T.; and Wong, P.Y.D. (2006) Post-meiotic
approaches to male contraception. Mol. Cell. Endocrinol., 250, 1-
213.
[43] Anawalt, B.D.; Bebb, R.A.; Bremner, W.J. and Matsumoto, A.M.
(1999) A lower dosage levonorgestrel and testosterone combination
effectively suppresses spermatogenesis and circulating gonadotro-
pin levels with fewer metabolic effects than higher dosage combi-
nations. J. Androl., 20, 407-414.
[44] Wu, F.C. (2006) Hormonal approaches to male contraception:
approaching reality. Mol. Cell. Endocrinol., 250, 2-7.
[45] Yin, D.; Gao, W.; Kearby, J.D.; Xu, H.; Chung, K; He, Y.; Marhe-
fka, G.A.; Veverka, K.A.; Miller, D.D. and Dalton, J.T. (2003)
Pharmacodynamics of selective androgen receptor modulators. J.
Pharmacol. Exp. Ther., 304, 1334-1340.
[46] Zhen, Q.S.; Ye, X. and Wei, Z.J. (1995) Recent progress in re-
search on Tripterygium: a male antifertility plant. Contraception,
51, 121-129.
[47] Lue,Y.; Sinha Hikim, A.P.; Wang, C.; Leung, A.; Baravarian, S.;
Sangsawan, R.; Chaichana, S. and Swerdloff, R.S. (1998) Triptol-
ide: a potential male contraceptive. J. Androl., 19, 479-486.
[48] Lohiya, N.K.; Manivannan, B.; Mishra, P.K.; Pathak, N.; Sriram,
S.; Bhande, S.S. and Panneerdoss, S. (2002) Chloroform extract of

Male contraception Endocrine, Metabolic & Immune Disorders - Drug Targets, 2010, Vol. 10, No. 2 9
Carica papaya seeds induces long-term reversible azoospermia in
langur monkey. Asian J. Androl., 4, 17-26.
[49] Kamal, R.; Gupta, R.S. and Lohiya, N.K. (2003) Plants for male
fertility regulation. Phytother. Res., 17, 579-590.
[50] Pathak, N.; Mishra, P.K.; Mannivannan, B. and Lohiya, N.K.
(2000) Sterility due to inhibition of sperm motility by oral admini-
stration of benzene chromatographic fraction of the chloroform ex-
tract of the seeds of Carica papaya in rats. Phytomedicine 7, 325-
333.
[51] Malorni, W.; Meschini, S.; Matarrese, P. and Arancia, G. (1992)
The cytoskeleton as a subcellular target of the antineoplastic drug
lonidamine. Anticancer Res., 12, 2037-2045.
[52] Cheng, C.Y.; Mruk, D.; Silvestrini, B.; Bonanomi, M.; Wong,
C.H.; Siu, M.K.; Lee, N.P.; Lui, W.Y. and Mo, M.Y. (2005) AF-
2364 [1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide]
is a potential male contraceptive: a review of recent data. Con-
traception, 72, 251-261.
[53] Mruk, D.; Wong, C.H.; Silvestrini, B. and Cheng, C.Y. (2006) A
male contraceptive targeting germ cell adhesion. Nat. Med., 12,
1323-1328.
[54] van der Spoel, A.C.; Jeyakumar, M.; Butters, T.D.; Charlton, H.M.;
Moore, H.D.; Dwek, R.A. and Platt, F.M. (2002) Reversible infer-
tility in male mice after oral administration of alkylated imino sug-
ars: a nonhormonal approach to male contraception. Proc. Natl.
Acad. Sci. USA, 99, 17173-17178.
[55] Tulsiani, D.R.P.; Zeng, H.T. and Abou-Haila, A. (2007) Biology of
sperm capacitation: evidence for multiple signalling pathways. Soc.
Reprod. Fert. Suppl., 63, 257-272.
[56] Ho, H.C.; Granish, K.A. and Suarez, S.S. (2002) Hyperactivated
motility of bull sperm is triggered at the axoneme by Ca2+ and not
cAMP. Dev. Biol., 250, 208-217.
[57] Darszon, A.; Acevedo, J.J.; Galindo, B.E.; Hernandez-Gonzalez,
E.O.; Nishigaki, T.; Trevino, C.L.; Wood, C. and Beltran, C.
(2006) Sperm channel diversity and functional multiplicity. Repro-
duction 131, 977-988.
[58] Ho, H.C. and Suarez, S.S. (2003) Characterization of the intracellu-
lar calcium store at the base of the sperm flagellum that regulates
hyperactivated motility. Biol. Reprod., 68, 1590-1596.
[59] Ren, D.; Navarro, B.; Perez, G.; Jackson, A.C.; Hsu, S.; Shi, Q.;
Tilly, J.L. and Clapham, D.E. (2001) A sperm ion channel required
for sperm motility and male fertility. Nature 413, 603-609.
[60] Quill, T.A.; Ren, D.; Clapham, D.E. and Garbers, D.L. (2001) A
voltage-gated ion channel expressed specifically in spermatozoa.
Proc. Natl. Acad. Sci. USA, 98, 12527-12531.
[61] Garbers, D.L. (2001) Ion channels. Swimming with sperm. Nature,
413, 581-582.
[62] Xia, J.; Reigada, D.; Mitchell, C.H. and Ren, D. (2007) CATSPER
channel-mediated Ca2+ entry into mouse sperm triggers a tail-to-
head propagation. Biol. Reprod., 77, 551-559.
[63] Quill, T.A.; Sugden, S.A.; Rossi, K.L.; Doolittle, L.K.; Hammer,
R.E. and Garbers, D.L. (2003) Hyperactivated sperm motility
driven by CatSper2 is required for fertilization. Proc. Natl. Acad.
Sci. USA, 100, 14869-14874.
[64] Carlson, A.E.; Quill, T.A.; Westenbroek, R.E.; Schuh, S.M.; Hille,
B. and Babcock, D.F. (2005) Identical phenotypes of CatSper1 and
CatSper2 null sperm. J. Biol. Chem., 280, 32238-32244.
[65] Avidan, N.; Tamary, H.; Dgany, O.; Cattan, D.; Pariente, A.;
Thulliez, M.; Borot, N.; Moati, L.; Barthelme, A.; Shalmon, L.;
Krasnov, T.; Ben-Asher, E.; Olender, T.; Khen, M.; Yaniv, I.;
Zaizov, R.; Shalev, H.; Delaunay, J.; Fellous, M.; Lancet, D. and
Beckmann, J.S. (2003) CATSPER2, a human autosomal nonsyn-
dromic male infertility gene. Eur. J. Hum. Gene. 11, 497-502.
[66] Naz, R.K. (1999) Vaccine for contraception targeting sperm.
Immunol. Rev. 171, 193-202.
[67] Tulsiani, D.R.P. and Abou-Haila, A. (2001) Mammalian sperm
molecules that are potentially important in interaction with female
genital tract and egg vestments. Zygote, 9, 51-69.
[68] O’Rand, M.G.; Widgren, E.E.; Wang, Z. and Richardson, R.T.
(2007) Eppin: an epididymal protease inhibitor and a target for
male contraception. Soc. Reprod. Fertil. Suppl., 63, 445-453.
[69] Guha, S.K. (1996), US Patent, 5488075.
[70] Chaudhury, K.; Bhattacharyya, A.K. and Guha, S.K. (2004) Studies
on the membrane integrity of human sperm treated with a new in-
jectable male contraceptive. Human Reprod., 19, 1826-1830.
[71] Koul, V.; Srivastava, A. and Guha, S.K. (1998) Reversibility with
sodium bicarbonate of styrene maleic anhydride, an intravasal in-
jectable contraceptive, in male rats. Contraception, 58, 227-231.
[72] Guha, S.K.; Singh, G.; Anand, S.; Ansari, S.; Kumar, S. and Koul,
V. (1993) Phase I clinical trial of an injectable contraceptive for the
male. Contraception, 48, 367-375.
[73] Guha, S.K.; Singh, G.; Ansari, S.; Kumar, S.; Srivastava, A.; Koul,
V.; Das, H.C.; Malhotra, R.L. and Das, S.K. (1997) Phase II clini-
cal trial of a vas deferens injectable contraceptive for the male.
Contraception, 56, 245-250.
[74] Song, L.; Gu, Y.; Lu, W.; Liang, X. and Chen, Z. (2006) A phase II
randomised controlled trial of a novel male contraception, an intra-
vas device. Int. J. Androl., 29, 489-495.
Received: 20 January, 2010 Accepted: 02 February, 2010