RISUG: A new perspective in non-hormonal male contraception

Abstract

Currently there are several hormonal and non-hormonal methods of contraception available but due to long term side effects of hormonal contraceptives, a great research is undergoing to develop an effective and noninvasive non-hormonal male contraceptive. One of the product of this research is RISUG (an acronym for the Reversible Inhibition of Sperm Under Guidance). RISUG is a co-polymer of Styrene Maleic Anhydride (SMA) dissolved in Dimethyl Sulfoxide (DMSO) to form a gel. This gel is then introduced in the lumen of male vas deferens which results in the partial blockage of vas deferens. It causes the disruption of the membrane of spermatozoa and release of enzymes that are essential for the fertilization of ova. Thus the ejaculation after RISUG contains infertile spermatozoa.

Keywords
Contraceptive; RISUG; Vas deferens; SMA; Fertilization; DMSO

Full text

159
Document heading
doi:
10.1016/S2305-0500(13)60138-4
RISUG: A
new perspective in non-hormonal male contraception
V
ikas
T
hakur
1
,
M
anjusha
C
houdhary
1
*
,
V
ineet
M
ehta
1
,
D
inesh
K
umar
1
,
N
itesh
2
1
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra-136119 Haryana, India
2
R. I. Inderprastha Institute of Technology, Karnal-132001, Haryana, India
ARTICLE INFO ABSTRACT
Article history:
Received 22 March 2013
Received in revised form 23 April 2013
Accepted 25 April 2013
Available online 20 June 2013
Keywords:
Contraceptive
RISUG
V
as deferens
SMA
F
ertilization
DMSO
*Corresponding author: Mrs. Manjusha choudhary, Institute of Pharmaceutical
Sciences, Kurukshetra University, Kurukshetra, Haryana, India.
Tel: +91-9991146283
E-mail: manjushachoudhary@gmail.com
1. Introduction
Today the huge growth of world population is one of the
biggest challenges faced by the human race.
In 1997 the
world population was
5.8 billion and currently it is around
7 billion and it is expected that it will be 8 billion by 2025,
9.1 billion in 2050 and 19 billion by the end of twenty first
century
[1,2]
. As the global population continuously increasing
very sharply, there is an urgent need to increase the choice
of effective contraception methods.
Indeed today we have
both hormonal and non-hormonal methods available for the
male contraception.
However the long term use of hormonal
contraceptives (androgen, progestin) might associate
with serious adverse reactions such as cancer, obesity,
hypertension and blood clotting.
Thus the non-hormonal
contraceptives might be more suitable than hormonal
contraceptives because they do not affect the functioning
of male sex organs such as prostate gland.
Currently many
non-hormonal male contraceptives are under various stages
of researc
h and development
[3]
.
2. Reversible inhibition of sperm under guidance
RISUG (Reversible Inhibition of Sperm Under Guidance),
is an injectable compound which has completed its phase
I and II clinical trial and now under phase III clinical trial
in
India
[4,5]
. It consists of a co-polymer of Styrene Maleic
Anhydride (SMA) dissolved in Dimethyl Sulfoxide (DMSO)
to form a gel.
This compound is injected into the lumen
of vas deferens by no scalpel
technique and provides
contraception for at least
8 to 10 years
[6]
.
3. Mechanism of action
RISUG is a poly electrolytic compound. It is introduced
in the lumen of vas deferens, where it comes in contact
with the spermatozoa
[7]
. On contact with the spermatozoa,
due to its poly-electrolytic nature, it cause ionic imbalance
on the human sperm membrane which results in swelling
and rupture of the sperm head
(Acrosome) and leakage
Currently there are several hormonal and non-hormonal methods of contraception available
but due to long term side effects of hormonal contraceptives, a great research is undergoing to
develop an effective and noninvasive non- hormonal male contraceptive.
One of the product
of this research is
RISUG (an acronym for the Reversible Inhibition of Sperm Under Guidance).
RISUG is a co-polymer of Styrene Maleic Anhydride (SMA) dissolved in Dimethyl Sulfoxide (DMSO)
to form a gel.
This gel is then introduced in the lumen of male vas deferens which results in the
partial blockage of vas deferens.
It causes the disruption of the membrane of spermatozoa and
release of enzymes that are essential for the fertilization of ova.
Thus the ejaculation after RISUG
contains infertile spermatozoa.
Asian Pacific Journal of Reproduction 2013; 2(2): 159-162
Asian Pacific Journal of Reproduction
Journal homepage: www.apjr.net

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Vikas Thakur et al./ Asian Pacific Journal of Reproduction (2013)159-162
of enzymes (Hyaluronidase and Acrosin) necessary for the
fertilization of ova
[8]
. RISUG results in partial blockage
of vas deferens associated with the flow of functionally
inactive cells
[9]
. The RISUG ejaculates consist of partially
or completely damaged spermatozoa which functionally
become unable to fertilize the ova.
The earlier studies
carried over langur monkeys have shown that vas deferens
with
SMA results in severe oligospermia or azoospermia
in first two ejaculations and continuous azoospermia in
subsequent ejaculations
[10]
. Release of enzymes necessary
for fertilization is discussed in
Figure 1.
Sperm membrane disruption after interaction
with RISUG
Neck
Acrosome
Head
Midpicec
tail
Figure 1.
Membrane disruption and release of enzymes which are
necessary for fertilization.
4.
RISUG
administration
The RISUG is administered into the vasa deferens by
using a non-scalpel method and requires only
15 minutes
to complete the procedure.
Once the RISUG administered
into the lumen of vas deferens, it fixed firmly to very small
folds on the inner surface of vas deferens with in
72 hour
of injection
[11]
. In first clinical trial of RISUG, it is found
that the therapeutic dose of the drug
is 60 milligram
[12]
. The
persons who had administered the drug in second clinical
trial have now been using the drug for more than
10 or 15
year without any problem.
After the proper implantation of
the drug, there is no pregnancy found to occur during the
1-3 year of the clinical study
[4]
. RISUG injection into vas
deferens has been described diagrammatically in
Figure 2.
Bladder
Vas deferens
Penis
Scrotum
Seminal vesicle
Rectum
Urethral sphincter
Sperms in vas deterens
interact with RISUG and
loose their capacity to
fertilize the egg
Sperm
Figure 2.
RISUG injection into vas deferens.
5.
RISUG
reversal
Earlier studies in primates have shown that RISUG is
easily reversible.
The studies have been shown that multiple
injections and reversal is effective in primates
[13]
. The
noninvasive reversal of
RESUG is obtained by flushing
it out from the lumen of vas deferens by dissolving in an
appropriate solvent
[14]
. It can also be removed by stimulating
the vas deferens percutaneously
[15]
. In one of study it is
reported that an injection of baking soda
dissolved in water
flush out the drug from the vas deferens effectively
[14]
.
Another study showed the effective removal of the RISUG
from the lumen by massage, vibration and low electrical
current
[16]
. The study on primates put forward that it
would take some months for the whole reversal of
RISUG
’
s
contraceptive effects
[17]
. Unlike vasectomy, RISUG does not
cause any kind of auto-immune response and its reversal is
very much trustworthy
[18]
.
6. Other reported activity
In addition to contraception, RISUG has also shown to
possess antimicrobial activity.
The research has proven
that
RISUG possesses potent antimicrobial activity against
a number of microorganisms such as
C
andida albicans,
P
seudomonas aeruginosa,
S
taphylococcus aureus,
E
scherichia
coli, and
N
eisseria gonococci
[20]
. The viruses are more
susceptible to its antimicrobial action than the vegetative
form of bacteria such as
S
taphylococcus and
P
seudomonas.
The drug has shown to possess anti-HIV activity due to its
electrical charge effect
[19,20]
.
7. Future prospective
RISUG is a polymeric complex of SMA and DMSO
[8,21]
. On
its administration
into the lumen of vas deferens, it reacts
with the water molecule, lipids and proteins present in the
spermatic fluid resulting in gel formation.
Progressively the
SMA gets converted into styrene maleic acid and mandelic
acid.
The mandelic acid and styrene maleic acid (SMAac)
which are released from the
RISUG implant gradually
moves with the spermatic fluid along the vas deferens to the
ejaculato
ry duct and to the semen. The SMA and mandelic
acid mix with the spermatic fluid and deactivate the
HIV
present in the semen
[20]
. The anti-HIV activity of mandelic
acid has been already proven
[21]
. Thus it helps to clear
the semen from
HIV virus. Another proposed additional

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Vikas Thakur et al./ Asian Pacific Journal of Reproduction (2013)159-162
action is through hyaluronidase, released during the
acrosome reaction.
An increase in the number of acrosome
reacted sperms result in increase in the concentration of
hyaluronidase enzyme in spermatic fluid. Hyaluronidase
acts over tissue collagen protein and facilitates the entry
of
HIV virus into tissue
[20,22]
. Hyaluronidase increases the
penetration of
HIV virus into the tissues thus HIV absorbs in
to the surrounding tissue from the seminal fluid.
Ultimately
the seminal
HIV load will further reduce and the whole
semen will be free from the
HIV. The foremost problem
of antiretroviral therapy is
that most of the host body
reservoir are resistant to the entry of anti-
HIV drugs. The
hyaluronidase will increase the absorption of virus into the
nearby tissue and not to the structures from which the virus
is instigated.
Now the tissue containing the virus is likely to
be less protected to the action of anti-
HIV drugs and results
in the greater exposure of the virus to the drug at low dose
and thereby produces lesser side effects
[20]
.
8. RISUG: as an entry inhibitor for HIV
Entry inhibitors are the type of antiretroviral drug that
inhibit the entry of
HIV into the host immune cells. A
hypothesis is set forward in which a new non-hormonal male
contraceptive,
RISUG with confirmed antimicrobial activity
is recommended as a potential entrant for entry inhibitor
group of antiretroviral drugs.
The suggested mechanism
of action of
RISUG includes (1) it interacts with the gp120
(a viral surface protein) and thus prevents the binding of
the virus to the cell surface of
CD4 helper T cells and (2)
competitively binds with viral surface glycoprotein and thus
prevents the glycoprotein
-
cell surface glycosaminoglycan
Heparan Sulfate(HS)
[23]
. Possible mechanism of action of
RISUG as an entry inhibitor, anti-retroviral drug is given in
Figure 3.
Figure 3.
Possible mechanism of action of RISUG as an entry inhibitor, anti-retroviral drug.
9. Expected side effects of RISUG
In phase II clinical trial some participants showed minor
swelling of testes with no concomitant pain.
The swelling
resolved within
2 weeks after injection of RISUG without
any treatment
[24]
. Unlike vasectomy RISUG does not show
autoimmune response and granulomas
[18]
. Another fear
accompanying vas deferens occlusion is declined prostate
gland health.
But men from phase II clinical trial 8 years
after receiving the
RISUG had healthy prostate
[25]
.
10. Conclusions
Today the RISUG is under extensive research and
development and in clinical phase
III trial in India. The
conventional hormonal contraceptives produce numerous
side
effects on their long term use. The non-hormonal male
contraceptive RISUG provides effective contraception
without producing any type of serious adverse reactions. In
addition to contraceptive activity it is proposed that the drug
may be having anti-
HIV activity. Thus RISUG might be a
potential non-hormonal contraceptive in upcoming years.
Conflict of interest statement
We declare that we have no conflict of interest statement.
HIV-1(gp120)
RISUG
interaction with cell
suface HSPG
accomulation of
viruses cell surface
RISUG
CD4 helper cell
CD4/gp120 interaction
Fusion with cell
infected cell with HIV
Cell death

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Vikas Thakur et al./ Asian Pacific Journal of Reproduction (2013)159-162
References
[1] Oxynos C, WCF Wu. Male hormonal contraception. Bailliere
’
s
Clin Endocrinol Metab 2000;
14
:
473-487.
[2] Jose Antonio Ocampo. Population studies: World population
prospect. New York: United Nation; 2002.
[3] Mruk DD. New persepectives in non-hormonal male
contraception. Trends Endocrin Met 2008;
19
:
57-64.
[4] Guha SK. Contraceptive for use by a male. USA patent 1996: No.
5488075.
[5] Guha SK, Singh G, Anasari S, Kumar S, Srivastava A, Koul V.
Phase II clinical trial of a vas deferens injectable contraceptive
for the male. Contraception 1997;
56
(4): 245-250.
[6] Sohini R, Ghosh D, Guha SK. Polyelectrolyte polymer properties
in relation to male contraceptiveRISUG
®
action. Colloids Surf B
2009;
69
:
77-84.
[7] Kumar S, Chaudhury K, Sen P, Guha SK. Topological alteration
in human spermatozoa associated with the polyelectrolytic effect
of RISUG. Micron 2006;
37
:
526-532.
[8] Chaudhry K, Bhattacharyya AK, Guha SK. Studies on membrane
integrity of human sperm treated with a new injected male
contraceptive. Hum Repord 2004;
19
:
1826-1830.
[9] Chaudhury K, Sharma U, Jagannathan NR, Guha SK. Effect of a
new injectable male contraceptive on the seminal plasma amino
acids studied by proton NMR spectroscopy. Contraception 2002;
66
:
199-204.
[10] Lohiya NK, Manivannan B, Mishra PK. Ultrastructure changes in
the spermatozoa of langur monkeys
Presbytis entellus entellus
after
vas occlusion with styrene maleic anhydride. Contraception 1998;
57
:
125-132.
[11] Guha SK. Biophysical mechanism-mediated time-dependent
effect on sperm of human and monkey vas implanted
polyelectrolyte contraceptive. Asian J Androl 2007;
9
(2): 221-
227.
[12] Guha SK, Singh S, Anand S, Anasri S, Kumar S, Koul V. Phase
I clinical trial of an injectable contraceptive for the male.
Contraception 1993;
48
(4): 367-375.
[13] Lohiya NK, Manivannan B, Mishra PK. Repeated vas occlusion
and non-invasive reversal with styrene maleic anhydride for male
contraception in langur monkeys. Int J Androl 2000;
23
(1): 36-
42.
[14] Koul V, Srivastva A, Guha SK. Reversibility with sodium
bicarbonate of styrene maleic anhydride, an intravasal injectable
contraceptive, in male rats. Contraception 1998;
58
(4): 227-234.
[15] Guha SK. Non-invasive reversal of intraluminal vas deferens
polymer injection induced azoospermia--technology. Asian J
Androl 1999;
1
:
131-134.
[16] Lohiya NK, Manivannan B, Mishra PK. Ultrastructural changes
in the spermatozoa of langur monkeys Presbytis entellus entellus
after vas occlusion with styrene maleic anhydride. Contraception
1998;
57
(2): 125-132.
[17] Lohiya, NK, Manivannan B, Mishra PK, Sriram S, Bande SS,
Panneerdoss S. Preclinical evaluation for noninvasive reversal
following long-term vas occlusion with styrene maleic anhydride
in langur monkeys. Contraception 2005;
71
(3): 214-226.
[18] Mishra PK, manivannan B, Pathak N, Bhande SS, Panneerdoss
S. Status of spermatogenesis and sperm parameters in langur
monkeys following long-term vas occlusion with styrene maleic
anhydride. J Androl 2003;
24
(4): 501-509.
[19] Favero MS, Bond WV. Chemical disinfection of medical and
surgical materials. In: Block SF, (ed). Disinfection, sterilization
and preservation. Philadelphia: Lea & Febiger; 1991, p. 621.
[20] Guha SK. RISUG_ (reversible inhibition of sperm under
guidance)
-
An antimicrobial as male vas deferens implant for
HIV free semen. Medical hypothesis 2005;
65
:
61-64.
[21] Herold BC, Scordi-Bello I, Cheshenko N. Mandelic acid
condensation polymer: noval candidate microbicide for prevention
of human immunodeficiency virus and herpes simplex virus entry.
J Virol 2002;
76
(22): 11236-11244.
[22] Favre D, Cherel Y, Provost N, Blouin V. Hyaluronidase enhances
recombinant adeno-associated virus (rAAV)-mediated gene
transfer in the rat skeletal muscle. Gene Ther 2000;
7
(16): 1417-
1420.
[23] Guha SK, Banerjee S. RISUG: A potential candidate for the entry
inhibitor group of antiretroviral drugs. Medical Hypothesis 2009;
73
:
150-152.
[24] Guha SK, Singh G, Ansari S, Kumar S, Sirivastva A, Koul V.
Phase II clinical trial of a vas deferens injectable contraceptive
for male. Contraception 1997;
56
:
245-250.
[25] Sharma U, Chaudhury K, Jagannathan NR, Guha SK. A
proton NMR study of the effect of a new intravasal injectable
male contraceptive RISUG on seminal plasma metabolites.
Reproduction 2001;
122
:
431-436.