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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
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Document heading
new perspective in non-hormonal male contraception
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra-136119 Haryana, India
R. I. Inderprastha Institute of Technology, Karnal-132001, Haryana, India
Article history:
Received 22 March 2013
Received in revised form 23 April 2013
Accepted 25 April 2013
Available online 20 June 2013
as deferens
*Corresponding author: Mrs. Manjusha choudhary, Institute of Pharmaceutical
Sciences, Kurukshetra University, Kurukshetra, Haryana, India.
Tel: +91-9991146283
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
. 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
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
. 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
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
. 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:
Vikas Thakur et al./ Asian Pacific Journal of Reproduction (2013)159-162
of enzymes (Hyaluronidase and Acrosin) necessary for the
fertilization of ova
. RISUG results in partial blockage
of vas deferens associated with the flow of functionally
inactive cells
. 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
SMA results in severe oligospermia or azoospermia
in first two ejaculations and continuous azoospermia in
subsequent ejaculations
. Release of enzymes necessary
for fertilization is discussed in
Figure 1.
Sperm membrane disruption after interaction
with RISUG
Figure 1.
Membrane disruption and release of enzymes which are
necessary for fertilization.
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
. In first clinical trial of RISUG, it is found
that the therapeutic dose of the drug
is 60 milligram
. 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
. RISUG injection into vas
deferens has been described diagrammatically in
Figure 2.
Vas deferens
Seminal vesicle
Urethral sphincter
Sperms in vas deterens
interact with RISUG and
loose their capacity to
fertilize the egg
Figure 2.
RISUG injection into vas deferens.
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
. The
noninvasive reversal of
RESUG is obtained by flushing
it out from the lumen of vas deferens by dissolving in an
appropriate solvent
. It can also be removed by stimulating
the vas deferens percutaneously
. 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
Another study showed the effective removal of the RISUG
from the lumen by massage, vibration and low electrical
. The study on primates put forward that it
would take some months for the whole reversal of
contraceptive effects
. Unlike vasectomy, RISUG does not
cause any kind of auto-immune response and its reversal is
very much trustworthy
6. Other reported activity
In addition to contraception, RISUG has also shown to
possess antimicrobial activity.
The research has proven
RISUG possesses potent antimicrobial activity against
a number of microorganisms such as
andida albicans,
seudomonas aeruginosa,
taphylococcus aureus,
coli, and
eisseria gonococci
. The viruses are more
susceptible to its antimicrobial action than the vegetative
form of bacteria such as
taphylococcus and
The drug has shown to possess anti-HIV activity due to its
electrical charge effect
7. Future prospective
RISUG is a polymeric complex of SMA and DMSO
. 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
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
ry duct and to the semen. The SMA and mandelic
acid mix with the spermatic fluid and deactivate the
present in the semen
. The anti-HIV activity of mandelic
acid has been already proven
. Thus it helps to clear
the semen from
HIV virus. Another proposed additional
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
HIV virus into tissue
. Hyaluronidase increases the
penetration of
HIV virus into the tissues thus HIV absorbs in
to the surrounding tissue from the seminal fluid.
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
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
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)
. 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
. Unlike vasectomy RISUG does not show
autoimmune response and granulomas
. 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
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
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.
interaction with cell
suface HSPG
accomulation of
viruses cell surface
CD4 helper cell
CD4/gp120 interaction
Fusion with cell
infected cell with HIV
Cell death
Vikas Thakur et al./ Asian Pacific Journal of Reproduction (2013)159-162
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ÖZET Amaç: Bu araştırma, tedaviye başvuran infertil kadınlarda kaygı düzeyi ve etkileyen faktörleri incelemek amacıyla yapılmıştır. Materyal ve Metod: Tanımlayıcı ilişki arayıcı nitelikte olan bu çalışma, Ondokuz Mayıs Üniversitesi Tıp Fakültesi Tüp Bebek Merkezinde Ocak-Mayıs 2014 tarihleri arasında yapılmıştır. Çalışmanın örneklemini ise, tüp bebek merkezine başvuran uzmanlar tarafından yapılan jinekolojik değerlendirme sonucunda primer veya eş kaynaklı infertilite tanısı almış olan, olasılıksız örnekleme yöntemiyle seçilen, araştırmaya katılmayı gönüllü kabul eden toplam 287 infertil kadın oluşturmuştur. Verilerin toplanmasında kişisel bilgi formu ve Spielberger durumluk-sürekli kaygı envanteri kullanılmıştır. Veriler bu formlar aracılığıyla aracılığıyla yüz yüze görüşülerek toplanmıştır. Verilerin analizinde tanımlayıcı istatistikler, Mann-Whitney U-testi ve Kruskal-Wallis testi kullanılmıştır. Bulgular: Çalışmayan, çekirdek aile yapısına sahip olan, 11 yıl ve daha fazla süredir evli olan, görücü usulüyle isteyerek evlenen, evlilik hayatını "iyi" olarak değerlendiren kadınların durumluk kaygı düzeylerinin daha yüksek olduğu saptanmıştır (p<0.05). Geliri giderine denk olan kadınların ise durumluk ve sürekli kaygı puanları anlamlı şekilde daha yüksek bulunmuştur (p<0.05). Daha önce infertilite tedavisi alınması durumu, infertilite tedavisi konusunda bilgisi olma durumu, kullanılan tedavi yöntemi ile durumluk kaygı puanları arasında istatistiksel olarak anlamlı bir fark tespit edilmiştir (p<0.05). İnfertilitenin kaynaklandığı kişinin durumluk kaygı düzeyini etkilemediği fakat, sürekli kaygı düzeyini anlamlı düzeyde etkilediği saptanmıştır (p<0.05). Sonuç: İnfertilite tedavisi gören kadınların durumluluk kaygı puan ortalaması 45.1±9.4 ve sürekli kaygı puan ortalaması 46.0±7.7 olarak yüksek kaygı düzeyine sahip oldukları bulunmuştur. İnfertilite tedavisi alan kadınların kaygı durumları ve etkileyen faktörlerin bilinmesi uygun hemşirelik girişimlerinin zamanında planlanması ve kadınların olası problemler ve kaygı problemlerini en az düzeyde yaşaması açısından önemlidir. ABSTRACT Objective: This study in women undergoing infertility treatment is carried out to investigate the effect of some variables related to the anxiety state of being infertile. Materials and Methods: This study which is descriptive nature of relations detectors, Ondokuz Mayıs University Faculty of Medicine IVF Center was made during the dates between January- May 2014. The sample of the study, in vitro fertilization and primary gynecological evaluation made by experts who applied to the center or co-sourced, which had been diagnosed with infertility, selected by unprobability sampling method, formed voluntarily accepting a total of 287 infertile women to participate in research. The data were collected personal information form and Spielberger state-trait anxiety inventory were collected through face to face interviews. In analyzing the data, descriptive statistics, Mann-Whitney U-test and Kruskal-Wallis test was used. Results: Inoperative, with the nuclear family, who have been married for more than 11 years and, arranged marriage willingly married, married life as "good" was found to be higher in women evaluates state anxiety levels (p<0.05). The women with income equivalent to resolve state and trait anxiety scores were significantly higher(p<0.05). Before taking the case of infertility treatment, infertility treatment information on the situation to be a statistically significant difference between state anxiety scores and the treatment method used it has been identified (p<0.05).Women 34.1% is self-caused infertility is caused by the wife mentioned that 24% of the people that caused infertility but does not affect the state anxiety, trait anxiety level was found to significantly affect (p<0.05). Conclusion: The women undergoing infertility treatment trait anxiety mean score of 45.1 ± 9.4 and mean trait anxiety scores were found to have high levels of anxiety as 46.0 ± 7.7. Nurses should know the factors on anxiety levels of İnfertile women during treatment and the protocols for the women on the infertile treatment especially for the timing. Then, Women face lowered problems caused anxiety.
Full-text available
Changes in the physical characteristics of semen and ultrastructure of the spermatozoa of langur monkeys after vas occlusion with styrene maleic anhydride (SMA), a polymer with pH-lowering action, are reported. Vas occlusion resulted in severe reversible hypospermia. Severe oligospermia was observed in the majority of animals (five of eight) in the first ejaculation, 30 days after vas occlusion, and in two animals in the second ejaculation, 60 days after vas occlusion. Subsequent monthly ejaculations for 5 months revealed uniform azoospermia. The voided spermatozoa were immotile and supravital staining confirmed necrospermia. Scanning electron microscopy (SEM) revealed severe coiling of tail, rupture of acrosomal envelope, and bent midpiece associated with damaged mitochondrial sheath. Observations by transmission electron microscopy (TEM) revealed vacuolization in the nucleus, membrane damage in the acrosome, loss of segmented columns, and numeric aberrations in the centriole of the neck, as well as degeneration of mitochondrial sheath and axoneme in the midpiece, and absence of outer plasma membrane in the midpiece and tail. The results indicate that the necrospermic status of the spermatozoa during initial ejaculations may offer instant sterility after vas occlusion with SMA.
Full-text available
Skeletal muscle is a privileged target for long-term rAAV-mediated gene transfer in mouse, rat, dog and non-human primates. Intramuscular injections of rAAV encoding human factor IX in hemophilia B patients have been initiated, based on promising results gathered in affected dogs. We found that intramuscular rAAV administration in rats resulted in restricted transduction essentially along the myofibers axis with poor lateral diffusion. This suggested that the transduction rate might be limited by the ability of the virus to reach sites distant from the injection point. We tested whether hyaluronidase, an enzyme which dissociates the extracellular matrix, could enhance vector diffusion when injected in the rat muscle before administration of rAAV encoding either nuclear-localized beta-galactosidase (rAAVCMVnlsLacZ) or the human alpha-1-antitrypsin (rAAVCMVhAAT) under the control of the cytomegalovirus immediate--early promoter (CMV). The results showed that pretreatment of the rat anterior tibialis muscle with hyaluronidase resulted in: (1) a larger diffusion of the virus indicated by an increase in the area containing LacZ-transduced fibers, and (2) a two- to three-fold increase of transduction efficiency measured by the number of LacZ-positive fibers or by the hAAT serum concentration. We also provide evidence that hyaluronidase was well tolerated and was not associated with short- or long-term toxicity evaluated by morphological studies. Finally, in our experimental conditions, hyaluronidase did not promote rAAV dissemination to other organs as assessed by PCR to detect vector sequences. We conclude that pretreatment of skeletal muscle by hyaluronidase, a clinically available reagent, was harmless and resulted in a consistent and significant increase in rAAV diffusion and transduction levels.
This study investigated the role of oral contraception use versus nonuse as a moderator variable differentially influencing cognitive-emotional processes. Seventy-six healthy women (29 users and 47 nonusers; 18 to 48 years old), completed the State-Trait Anger Expression Inventory, the Clinical Analysis Questionnaire, the Rotter Scale of locus of control, the Daily Hassles Scale, and a Repertory Grid. A subsample (N = 33) also volunteered for a blood draw. Hormonal levels of progesterone and estrogen mostly were unrelated to cognitive and emotional measures, and contraindicated the "chemical suppression" proposition. Alternatively, when cognitive-emotional functioning was examined separately for users and nonusers, cognitive factors including the appraisal of stress, loci of control, and self-integration were implicated with specific patterns of negative affect and much more so for users than for nonusers. For the most part, oral contraceptive use versus nonuse seemed to influence the saliency rather than the nature of cognitive-emotional patterns. Discussion focused on oral contraceptive use as a moderator variable and the need for longitudinal research to clarify the evolving, biopsychosocial influence of hormonal regulatory treatment.
Entry inhibitors are a group of antiretroviral drug which prevents HIV from entering human immune cells. They include both fusion and attachment inhibitors. A hypothesis is put forward in which a new male contraceptive drug with proven antimicrobial property is proposed as a possible candidate for the entry inhibitor group of antiretroviral drugs. The proposed mechanism of action involves (i) interaction with gp120 and thereby preventing binding to CD4 and (ii) competitive binding with the viral glycoprotein and inhibit the glycoprotein - cell surface glyocosaminoglycan Heparan Sulfate (HS) interaction. A new drug RISUG (Reversible Inhibition of Sperm Under Guidance) presently undergoing Phase III clinical trials throughout India for its contraceptive effect in male has also antimicrobial actions. RISUG is a chemical complex of styrene maleic anhydride (SMA(AN)) and dimethyl sulfoxide. On injection into the vas deferens, it reacts with the components of intravas fluid, the spermatic fluid and gets converted to styrene maleic acid (SMA(AC)) and breakdown products like mandelic acid. An anti HIV activity of RISUG is likely due to its electrical charge and mandelic acid generation. For experimental validation HIV in vitro assays can be performed which will involve infectivity assays, luciferase assay and soluble gp120 assays. A positive result from the studies will validate the hypothesis.
RISUG a polyelectrolytic hydrogel (styrene maleic anhydride and dimethyl sulfoxide) has proven to be efficacious as a contraceptive for a long term when injected into the lumen of vas deferens. Currently it is in advanced phase III clinical trials in India. Present investigation analyzes the swelling characteristics of RISUG hydrogel in different pH buffers and various biological fluids to understand its retention in the vas deferens as reported in previous studies. Significant variation in degree of swelling and equilibrium swelling ratio with transformation of Fickian to non-Fickian mode of diffusion was observed with increased pH. This might be due to ionization of carboxylic groups at high pH resulting in increased electrostatic repulsive force and high osmotic pressure inside the hydrogel network affecting its physical cross-linking and increases the free volume. Conversely, at low pH the dissociation of carboxylic group is limited making the hydrogel more stable. Interaction with various biomolecules present in various biological fluids was also studied. SEM, AFM and FTIR were used to analyze the topological and structural parameters of the polymer in different mediums. Loosening of structure and increasing porosity with significant adsorption of various biomolecules was observed. AFM revealed a significant change in overall roughness of polymer surface on interaction with different biological fluids. These observations suggest that the swelling and increased roughness will lead to increased resistance to sperm movement in the vas deferens.
Earlier studies on the rat and the monkey had demonstrated that an injection of styrene maleic anhydride (SMA) in a solvent vehicle of dimethyl sulphoxide (DMSO) into the lumen of the vas deferens is toxicologically safe and has contraceptive action. Phase I clinical trial was therefore undertaken on 38 male volunteers giving varying doses of SMA, ranging between 5 mg and 140 mg, into each vas deferens. A dose of 70 mg is the predicted therapeutic dose based on animal data. That the compound is within the vas deferens lumen during the period of the safety assessment is inferred from the effect on the spermatozoa count in ejaculates which reach azoospermic levels in the higher dose ranges. The treatment is well tolerated with only minimal side effects in a few cases and no long-term adverse effects.
Following up on an earlier clinical trial demonstrating the safety of an intra-vas deferens injection of a contraceptive drug named Risug, comprised of styrene maleic anhydride (SMA) in a solvent vehicle of dimethylsulphoxide (DMSO), a study to assess the contraceptive effectiveness of a specific dose (60 mg) of SMA bilaterally was planned and implemented. Male subjects and their wives with normal reproductive profiles were the volunteer subjects. The wives were not using any contraceptives. The results reconfirm the safety and show that for a period of at least 1 year, the treatment leads to azoospermia in the male and gives pregnancy protection. PIP A Phase I clinical trial documented the safety of an intra-vas deferens injection of a contraceptive agent (Risug) containing up to 140 mg of styrene maleic anhydride (SMA) in a solvent vehicle of dimethylsulfoxide. This Phase II study sought to determine whether a single injection of a fixed dose of SMA into the lumen of the vas deferens controls fertility for a period of at least 12 months. 12 male subjects whose wives were not using a contraceptive method were administered 60 mg of SMA bilaterally. This regimen produced sustained azoospermia in all 12 subjects, with no changes in other parameters over the course of the 12-month study period. Spermatozoa all along the length of the vas deferens appeared to be inactivated immediately following injection. No pregnancies were reported. The findings confirm the safety of this method and indicate that the treatment leads to azoospermia for at least 1 year.
A copolymer of styrene and maleic anhydride (SMA) was dissolved in dimethyl sulphoxide (DMSO) and injected into the lumen of the vas deferens of rats. The polymer was retained in the lumen for a period of more than 90 days. Sodium bicarbonate (10%), pH 8.9, was used to flush the polymeric material from the vas deferens lumen. The reversibility and patency of the vas deferens was thus obtained. Sodium bicarbonate proved to be an effective alternative to dimethyl sulphoxide for reversal.
The feasibility of a spacing method for contraception, using Styrene Maleic Anhydride (SMA) as a vas occlusive agent, has been assessed in male langur monkeys. The vas deferens of 6 animals were occluded with 60 mg SMA in 120 microL DMSO. After 150 days, the occlusion was reversed by a technique which involved palpation, percutaneous electrical stimulation, forced vibratory movement, suprapubic percussion and per-rectal digital massage of the vas segments. The vas deferens were then re-occluded with SMA and reversed by the non-invasive method after three consecutive azoospermic samples. The second vas occlusion resulted in uniform azoospermia after the third ejaculation and reversal caused the reappearance of spermatozoa in the semen to severe oligozoospermic levels in the first two ejaculations and rising to normospermia in the subsequent ejaculations. Ultrastructure of the spermatozoa by SEM and TEM and sperm function tests revealed that the spermatozoa had recovered normal morphology. Vas morphology also regained a normal pseudostratified columnar epithelium containing basal and principal cells. The results suggest that the SMA-based spacing technique for male contraception could be extrapolated to the human by use of no-scalpel injection and non-invasive reversal.