By: Akanksha

Dr. Sujoy Kumar Guha is an Indian scientist who has spent the last fifty years waiting for the world to accept a  revolutionary medical breakthrough with global implications for both humans and animals. 

In 2020, he was awarded the Padma Shri, India’s fourth-highest civilian honor, in recognition of his pioneering contributions to science and engineering . 

Although RISUG has demonstrated contraceptive efficacy in human clinical studies, its proposed reversibility has not been established in humans. Clinical-trial results alone do not establish marketing authorization.

Born in Patna on June 20th 1940, Guha pursued his undergraduate degree (B. Tech) in electrical engineering at the Indian Institute of Technology (IIT) Kharagpur. He followed with a master’s degree in electrical engineering at IIT, and a second master’s degree from the University of Illinois, Urbana-Champaign. Bridging the gap between engineering and medicine,  Guha later earned a PhD in medical physiology from St. Louis University and subsequently completed an MBBS degree from the University College of Medical Sciences, University of Delhi. 

As one of the founding fathers of biomedical engineering in India, Dr. Guha established the Center of Biomedical Engineering at IIT Delhi. He is internationally recognized for his work in rehabilitation engineering, bioengineering in reproductive medicine, and accessible technology for rural healthcare.  

Over the course of his career, Dr. Guha has received numerous prestigious awards and published more than 100 research papers in reputable scientific journals. In 2003, he was appointed as a Chair Professor at IIT Kharagpur. On the manufacturing front, Professor Guha’s technological innovations helped establish a strong domestic production base for female contraceptives in India, including the Copper T and the Fallopian Tube Occlusion Ring. His magnum opus remains the invention and development of RISUG (Reversible Inhibition of Sperm Under Guidance) – a non-hormonal, polymer based injectable male contraceptive. 

What is RISUG Made Of? 

According to the patent documentation, the contraceptive is formulated as an injectable fluid containing a synthetic copolymer — styrene maleic anhydride (SMA) — dissolved in a dimethyl sulfoxide (DMSO) solvent.¹

1. Synthesis: the copolymer is prepared via cobalt-60 gamma irradiation of the monomers styrene and maleic anhydride in the presence of nitrogen in ethyl acetate. This is conducted at a radiation dose of 0.2 to 0.24 megarad for every 40g of polymer, at a dose rate of 30 to 40 rad/sec.¹ 

2. Preparation: The final injectable solution is prepared by dissolving 60 mg of SMA in 120 µL of DMSO.¹

3. Solvent Properties: DMSO is strongly alkaline and hygroscopic, minimal concentrations have reported no cytotoxicity.¹ DMSO was specifically selected as the solvent because it facilitates the penetration of the polymer into the mucosal folds of the inner walls of the vas deferens and ensures its long term retention.²

Also Read: ‘Vas Madness’ Shows the Power of Messaging on Men’s Contraceptive Decisions

How Does an Injectable Polymer Actually Stop Sperm? 

While US patent reports note that the exact mechanism of the contraceptive is not yet exhaustively mapped and retains some ambiguity, multiple complementary mechanisms have been documented by Dr. Guha and subsequent researchers.¹ 

The mechanisms described below are proposed explanations of RISUG's action. Although experimental studies support the effects of SMA on sperm, the precise contribution of each proposed mechanism has not been conclusively established.

The Polyelectrolyte and Charge-Imbalance Hypothesis

According to Dr. Guha, when the anhydrous copolymer is injected into the vas deferens, it hydrolyzes in the presence of water molecules in the seminal fluid.¹

1. Charge Disruption: the formed hydrate generates a positive charge that attracts negatively charged sperm, altering the charge of the sperm membrane and causing a fatal structural imbalance.¹ Dr. Guha emphasized that a free-flowing charge would not have the same effect; instead, RISUG functions specifically through its membrane-bound positive charge.1 He also noted that excess water in the spermatid fluid can generate a loss of charge, an area requiring further study.¹

2. Osmotic Rupture: Another related hypothesis is that upon conversion to a hydrate, chloride ions are no longer kept out of the sperm cell. This allows water to rush in, causing the plasma membrane to swell and rupture.¹ 

pH and Protein Interaction

Inside the vas deferens, the hydrolyzed SMA creates an acidic environment with a pH of 4.0 to 4.5.² Within 72 hours of injection, RISUG forms electrically charged precipitates in the lumen and coats the inner walls of the vas deferens.² Because these precipitates have a positive charge and create a low-pH environment, researchers propose that sperm passing through the RISUG-treated vas deferens experience ionic and pH stress. This may contribute to acrosomal damage and impaired fertilizing ability.²

Further, upon injection, RISUG interacts with proteins naturally present in the spermatid fluid.² Polar amino acids react with the SMA-DMSO complex, creating a chemical instability that detaches DMSO from SMA while retaining the broken bond and polyelectrolyte nature of the polymer.² the resulting protein-SMA complex maintains a positively charged surface that acts on passing sperm, while the outer protein layer simultaneously protect that SMA from premature dissolution, providing long-term contraception.²

Essentially, this intervention is localized strictly to the vas deferens with no detectable systemic interaction with other parts of the body.³ In this way, it differs fundamentally from hormonal injectables contraceptives, which influence the broader endocrine and reproductive systems.³

Can a Long-Term Male Contraceptive Truly Be Reversed?  

Preclinical trials demonstrated both the high efficacy of RISUG and the feasibility of reversing the procedure: 

1. Sperm Morphology in Rats: A study on vas deferens occlusion with RISUG demonstrate 100% sterility within 15 days post-injection in rats.¹ Histological analysis provided evidence of extensive morphological aberrations in the sperm, including nuclear membrane damage in the acrosome, loss of segmented columns, numerical aberrations in the centriole of the neck, degeneration of the mitochondrial sheath and axoneme in the midpiece, and the absence of the plasma membrane in the midpiece and tail.¹

2. Histological Data in Primates: Later, Guha et al. presented histological data in monkeys showing alternations in the sperm plasma membrane, mitochondria, and structural components that inhibit fertilizing ability.² This provided evidence of contraceptive effects in animal models. However, findings in animals cannot establish the long-term safety or reversibility of RISUG in humans.²

3. Chemical Dissolution and Reversal: At a higher pH (ranging from 8 to 9), the components of RISUG destabilize, allowing the polymer to unbind from the walls of the vas deferens and dissolve easily.¹ Both DMSO and sodium bicarbonate (NaHCO₃) have been used to flush and dissolve SMA.¹ In rat models, reversal using NaHCO₃ resulted in an earlier resumption of fertility compared to DMSO, and the procedure was found to be safe, feasible, and successful up to the F1 generation.²

4. Non-Invasive Reversal in Primates: Because surgical or chemical reversal posed challenges, studies were also carried out in langur monkeys using a non-invasive reversal technique.^1,3 Complete reversal was achieved through percutaneous squeezing of the vas deferens, combined with the suprapubic percussion, and pre-rectal digital massage of the ampullary region of the vas to loosen the intravasal SMA deposits and flush them toward the urethra.¹ 

Also Read: Mother Raises Awareness After Teen’s Death from Brain Blood Clot Linked to Contraceptive Pill

Human Reversibility Remains Unproven

Despite promising reversal results in animal models, RISUG's reversibility has not been established in humans. A review of male contraceptive development reported that no human reversibility data had been published for RISUG.³ Until studies demonstrate that fertility can be restored after reversal, its description as a reversible contraceptive should be understood as a proposed benefit rather than a proven clinical outcome. This limitation is important for men considering a long-acting contraceptive method.

How Effective is RISUG in Human Clinical Trials? 

The human clinical trials for RISUG progressed through multiple phases to establish optimal dosing, safety, and long-term efficacy: 

With Phase III clinical trials of RISUG completed successfully without adverse side effects, necessary regulatory approval from the Drugs Controller General of India (DCGI) has been sought, and the contraceptive is awaiting final clearance.³ 

In an initial multicentric, limited Phase III clinical trials published in 2019, 139 married men (each with at least two children) received a single bilateral intraluminal vas injection of 120 µL of RISUG and were followed alongside their wives for six months.⁵ While six individuals did not achieve azoospermia due to an incomplete injection procedure — resulting in two pregnancies among their partners  — the remaining 133 participants achieved either severe oligospermia or azoospermia within a month post-injection, with 82.7% maintaining continuous azoospermia after the first month and the remaining 17.3% achieving complete azoospermia within three to six months.⁵ Most participants experienced temporary scrotal enlargement and mild scrotal and inguinal pain that resolved within one month without impairing routine physical activity or libido.⁵ 

Building on these findings, a larger perspective, open-label, non-randomized Phase III clinical trial published in 2023 evaluated RISUG across five centers in India over a seven year follow up period.⁴ Out of 315 healthy, sexually active  married men (aged 25 to 40 years) who received the injection, 5 were lost to follow-up and 7 were excluded due to protocol violations, leaving 303 participants and their wives in the final analysis.⁴ At 21 days post-injection, 77.2% of subjects achieved azoospermia and 13.5% showed oligospermia with non-motile sperm; overall the trial reported a 97.3% efficacy in pregnancy prevention.⁴ Although 41.9% of subjects reported low to moderate grade scrotal pain on the third day post-injection that disappeared within 2.5 months, clinical and laboratory examinations confirmed no serious adverse effects, urinary tract infections, or traces of albumin or sugar in the urine of the male participants or their partners throughout the follow-up period. 

Could RISUG Also Protect Against Bacteria and HIV? 

The cell-damaging properties of RISUG are not limited to spermatozoa; the polymer also damages bacteria and potentially viruses.¹

1. Bactericidal Activity: Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM) studies have illustrated that RISUG exerts a direct antibacterial effect on Escherichia coli.² Based on its SMA composition, RISUG hypothesized to demonstrate broad antimicrobial activity against microorganisms including Candida albicans, Pseudomonas aeruginosa, Staphylococcus aureus, and E. coli.² 

2. Female Contraceptive Adaptation:  Another derivative of styrene maleic anhydride — Poly(styrene-alt-maleic anhydride)-4-aminophenol — possesses bactericidal properties and is being investigated as a modified RISUG for females, acting simultaneously as a contraceptive and a bactericide.¹

3. Antiviral Applications: Researchers have suggested that viruses may be even more sensitive to the antimicrobial action of RISUG than bacteria.² Based on this mechanism, RISUG has been proposed as a potential as a potential candidate for developing antiretroviral drugs or serving as a vas deferens implant to ensure HIV-free semen in HIV-positive men.² 

Despite its clinical promise, several scientific, regulatory, manufacturing and implementation questions remain relevant to its development and potential introduction into public use.

Are Big Pharma and Social Stigma Holding Male Contraception Back? 

A major factor inhibiting the progress of RISUG is the lack of interest from pharmaceutical companies. While an international survey found that 83% of men across various countries were willing to use a male contraceptive. Pharmaceutical giants have remained reluctant to pursue the technology, fearing it would undercut the thriving global markets for female contraceptives and condoms, which are valued at billions of dollars annually.² RISUG initially attracted corporate interest, but manufacturers withdrew upon realizing it was an inexpensive, one-time procedure rather than a recurring revenue source.²

Beyond commercial considerations, societal attitudes remain a major hindrance. In a largely patriarchal society, it has historically been difficult to persuade men to share the physical responsibility of family planning.²

Why Did It Take 50 Years to Bring This Breakthrough to Light? 

In the documentary The Scientist Who Runs at Night, Dr. Guha stated that roughly around 15 years of his research were lost to “unjustified” bureaucratic delays. He recounted that when he first proposed a male contraceptive based on electrical charges, the scientific community laughed, questioning what connection could possibly exist between contraception and bioelectricity. 

Once the method proved successful in animal models, institutional opposition began in earnest: 

1. The Medical Degree Mandate: The primary roadblock was that Guha was an electrical engineer, not a physician. The Indian Council of Medical Research (ICMR) refused to permit human clinical trials for a drug developed by someone without a medical degree. In response, Guha enrolled in medical school in his thirties — teaching engineering classes at IIT Delhi at 7:00 a.m. before rushing to attend lectures as an MBBS student at the University College of Medical Sciences by 8:00 a.m.

2. Regulatory Moving Goalposts: Even after earning his medical degree, Dr. Guha faced persistent challenges, including concerns about polymer safety, shifting legal requirements for clinical manufacturing, initial false alarm warnings regarding albumin in urine tests, and extensive bureaucratic red tape. Coupled with chronic fundraising difficulties for a low-cost, single-use intervention, Dr. Guha’s half-century perseverance stands as one of the most remarkable stories in modern Indian medicinal history. 

The broader development history also illustrates why promising contraceptive research can take decades to translate into public use. Evidence of contraceptive efficacy must be considered alongside long-term safety, the ability to restore fertility if reversibility is claimed, regulatory review, manufacturing quality and practical acceptability.

References: 

1. Lok Sabha Secretariat. Lok Sabha Question: Unstarred Question No. 4347. Government of India. https://sansad.in/getFile/loksabhaquestions/annex/172/AU4347.pdf?source=pqals.

2. “RISUG: An Intravasal Injectable Male Contraceptive.” Indian Journal of Medical Research 140, suppl. 1 (2014): S63–S72. https://pmc.ncbi.nlm.nih.gov/articles/PMC7017607/.

3. Sharma, Radhey Shyam, Ajit Kumar Mathur, Rajeev Singh, Hem Chandra Das, Gulshan Jeet Singh, Devinder Pal Singh Toor, and Sujoy Kumar Guha. “Safety and Efficacy of an Intravasal, One-Time Injectable and Non-Hormonal Male Contraceptive (RISUG): A Clinical Experience.” Indian Journal of Medical Research 150, no. 1 (2019): 81–86. https://ijmr.org.in/risug-an-intravasal-injectable-male-contraceptive/.

4. Sharma, Radhey Shyam, Ajit Kumar Mathur, Hem Chandra Das, Balbir Singh Shah, Arvind Goyal, Kuldeep Chander Sharma, Subhash Abrol, Balram Sahoo, Nirmal Kumar Lohiya, and Trilok Chand Sadasukhi. “Phase-III Clinical Trial with an Intravasal Once Injectable Non-Hormonal Male Contraceptive-Reversible Inhibition of Sperm under Guidance (RISUG).” Andrology: Open Access 12, no. 5 (2023): 297. https://www.longdom.org/abstract/phaseiii-clinical-trial-with-an-intravasal-once-injectable-nonhormonal-male-contraceptivereversible-inhibition-of-sperm--103058.html 

5. Sharma, Radhey Shyam, Ajit Kumar Mathur, Rajeev Singh, Hem Chandra Das, Gulshan Jeet Singh, Devinder Pal Singh Toor, and Sujoy Kumar Guha. “Safety and Efficacy of an Intravasal, One-Time Injectable and Non-Hormonal Male Contraceptive (RISUG): A Clinical Experience.” Indian Journal of Medical Research 150, no. 1 (2019): 81–86. https://pmc.ncbi.nlm.nih.gov/articles/PMC6798614/

(OG/APC/MSM)