- Email: [email protected]
Male contraception: Prospects for sound and ultrasound
Accepted Manuscript MALE CONTRACEPTION: Prospects for Sound and Ultrasound Robert Sewak, Bettina Teng, Lee A. Learman, Charles H. Hennekens PII: DOI: Reference:
S0306-9877(17)30104-4 http://dx.doi.org/10.1016/j.mehy.2017.06.010 YMEHY 8591
To appear in:
Medical Hypotheses
Received Date: Revised Date: Accepted Date:
29 January 2017 23 May 2017 20 June 2017
Please cite this article as: R. Sewak, B. Teng, L.A. Learman, C.H. Hennekens, MALE CONTRACEPTION: Prospects for Sound and Ultrasound, Medical Hypotheses (2017), doi: http://dx.doi.org/10.1016/j.mehy. 2017.06.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Revised Draft May 23, 2017, for resubmission Medical Hypotheses MALE CONTRACEPTION: Prospects for Sound and Ultrasound Running title: Prospects for Male Contraception Contributors 1. RS, Robert Sewak Sc.D 2. BT, Bettina Teng, BA 3. LAL, Lee A. Learman, MD, PhD 4. CHH, Charles H. Hennekens, MD, DrPH
Department(s) and institution(s) Charles E. Schmidt College of Medicine and Wilkes Honors College, Florida Atlantic University
Corresponding Author: Charles H. Hennekens, MD, DrPH, First Sir Richard Doll Professor & Senior Academic Advisor to the Dean, Charles E. Schmidt College of Medicine, Florida Atlantic University, 2800 S. Ocean Blvd. PHA, Boca Raton, FL 33432, USA Phone: 561-393-8845, Cell: 561-213-9450, Email: [email protected]
Total number of figures: None Total number of photographs: None Source(s) of support: None Presentation at a meeting: None Conflicting Interest: Dr. Sewak, Ms. Teng, and Professor Learman report no disclosures. Professor Hennekens reports that he is funded by the Charles E. Schmidt College of Medicine of Florida Atlantic University. Professor Hennekens also reports that he serves as an independent scientist in an advisory role to investigators and sponsors as Chair or Member of Data and Safety Monitoring Boards for Amgen, AstraZeneca, Bayer, British Heart Foundation, Cadila, Canadian Institutes of Health Research, DalCor, Genzyme, Lilly, Regeneron, and the Wellcome 1
Foundation; to Aralez, Pfizer and their legal counsel; UpToDate and the United States (U.S.) Food and Drug Administration; receives royalties for authorship or editorship of 3 textbooks and as co-inventor on patents for inflammatory markers and cardiovascular disease that are held by Brigham and Women’s Hospital; has an investment management relationship with the WestBacon Group within SunTrust Investment Services, which has discretionary investment authority and does not own any common or preferred stock in any pharmaceutical or medical device company.
Keywords: male contraception, sound, ultrasound, sperm, motility
2
CONTRIBUTOR’S DETAILS
Contribution Details (to be ticked marked as applicable):
Contributor 1 Concepts
x
Design
x
Definition of intellectual content
x
Literature search
x
Contributor 2 Contributor 3 Contributor 4
x
x
x
x
x
x
Clinical studies Experimental studies
x
Data acquisition
x
Data analysis
x
Statistical analysis
x
Manuscript preparation
x
x
x
x
Manuscript editing
x
x
x
x
Manuscript review
x
x
x
x
Guarantor
x
Summary of work done by the contributors: Dr. Sewak conceived of the hypothesis and defined the intellectual content. All authors participated in the design, literature search, manuscript preparation, manuscript editing, and manuscript review. As Professor Hennekens is the corresponding author he will serve as guarantor.
3
ABSTRACT The worldwide human population growth rate, which doubled during the 20th century, as well as the increasing fertility rate, have contributed to an increasing and evolving emphasis on contraception. With respect to female contraceptive methods, many have been developed, marketed, and are widely available. In contrast, male contraception has been limited to condoms, which pose logistical challenges, and vasectomy, which is largely irreversible. The use of sound to achieve effective and safe male contraception is a promising but unproven hypothesis. Based on the existing and incomplete totality of evidence, we hypothesize that the combination of sound with a modified ultrasonic technique in a single system will provide a practical delivery method that merges all of the appropriate and prescribed frequencies to have spermicidal qualities that may result in effective and safe male contraception. It is also plausible that any experimental male contraceptive method that heats the testicles where they can no longer produce sperm offers the possibility of a favourable benefit to risk ratio. The single system combining sound with a modified ultrasonic technique includes an acoustically suitable pad to assure proper transmission and delivery without concern for injury from the ultrasound frequencies, an amplification and regulation module, a frequency source generator, the complementary heat created along with external and targeted directionality, and various transport methods, such as wired, wireless, or remote. This methodology also offers the ability to move quickly to prototype, achieve multiple patent crossovers, secure and employ commercially available technologies, and provide the opportunity for rapid regulatory approval worldwide. These concepts have been explored in basic research in many animal species as well as humans. To achieve an adequate totality of evidence, the test of this hypothesis requires further
4
basic research in humans to clarify the relevant mechanisms, clinical and observational epidemiologic studies to further explore the hypothesis, and large-scale randomized trials to detect the most plausible magnitude of benefits of this promising but unproven technology. It is plausible that this technology will represent a major breakthrough to combat world population growth. It is also plausible, that, to paraphrase Thomas Huxley, this beautiful hypothesis will be slain by ugly facts.
5
INTRODUCTION The worldwide human population growth rate, which doubled during the 20th century, as well as the increasing fertility rate, has contributed to the increasing emphasis on contraception. Population growth rate is highly dependent on the fertility rate and should this trend in continue, the world population may reach 9.3 billion in 2050 and 10.1 billion in 2100 (1), underscoring the importance of safe and effective contraception as an optimal method for population control. At present, the contraceptive choices available in the market are mainly related to women, while men are limited to condoms and vasectomy as methods of contraception. The former has, to some, an unacceptable failure rate and the latter is largely irreversible (6). Although multicultural studies have shown a relatively high acceptance for male contraception among men, with more than three-fourths of men expressing intent to use a contraceptive (7), with most men and women in various studies finding the concept of male contraception to be acceptable, limitations in male contraception are still present mainly due to biological factors. Indeed, prevention can be achieved without severe cessation of estrogen production in women, while in men, reducing spermatogenesis to prevent pregnancy is difficult to achieve without a severe impact on testosterone production (8). Since the advent of condoms and vasectomies in the mid-20th century, clinicians and public health officials have been exploring other options. For example, in 2005, Reversible Inhibition of Sperm Under Guidance (RISUG), a one-time injection which was supposedly both side effect-free and reversible, was introduced. Yet, RISUG did not go beyond testing and never made it to the marketplace (2). In 2013, reports of a pill that would stop the release of sperm by targeting proteins that help launch sperm remained unsuccessful (3). Scientists have worked on other concepts. By the end of 2015, Vasalgel, a scrotal injection that physically blocks the sperm from entering through the vas deferens, was to
6
be introduced, (4) although there are numerous limitations to this approach. By 2016, researchers isolated an enzyme that is only found in sperm that affects its motility, hoping to create a drug that will render the sperm immotile and unable to swim to the egg, which is hypothesized to be free of hormonal side effects (5).
The Hypothesis One novel approach to male contraception through sound remains a promising but unproven hypothesis. Despite an incomplete totality of evidence, the available, albeit limited data, provides support for the hypothesis.
EVALUATION OF THE HYPOTHESIS Background An ideal contraceptive for men should be easily available, inexpensive, reversible, and easy to use, along with minimal side effects and changes in libido. The concept of male contraception is relatively well received across the world. Indeed, most men and women in various multicultural studies find the idea of male contraceptive use to be an acceptable option. An available effective form of male contraception would create more contraceptive options besides hormonal pills, patches, rings, and implants for women, as well as condoms and vasectomies for men.
In discussions about male contraception, about half of men surveyed would be willing to use new male contraceptive methods. This figure varies by country and is often related to demographic variables which include the acceptability of using existing contraceptive options.
7
A daily pill was reported as most acceptable in many locations, followed by implants and injections. In a survey of self-selected participants interested in new male contraceptive options, 99% said they would use a new method, 72% of women said they would trust men to use a new method, and there was a preference for non-hormonal methods given by yearly injection or a daily pill (9). In most surveys, respondents clearly favored a reversible option as opposed to vasectomy.
Sound and Ultrasound to Achieve Male Contraception This novel technique utilizes sound energy in the audible range for management and control of male fertility, using only select sound frequencies to disrupt the motility of the maturing sperm, impacting their viability and life potential. For example, sound can be used to reduce or enhance fertility by controlling aspects of fertility/conception, including sterilization, contraception and enhancing conception potential. The technique directs sound energy at the spermatozoa and can either inhibit or enhance their motility and/or movement (10). The sound energy, the select frequencies, the level of intensity, type of the energy, as well as waveform configuration and treatment duration can be adjusted in relation to the desired outcome. By example, the amount of applied sound energy may be greater for disrupting, blocking and/or disabling sperm, as described; and may be reduced for guiding and/or promoting sperm movement. In either situation, the sound energy may optionally be applied: continuously, in single bursts or, pulsated, in accordance with requirements for both the application and the intended outcome. Sound energy may be viewed as being mechanical in that it consists of the vibration of molecules about their equilibrium positions. Furthermore, it is known and accepted that the
8
application of sound energy on biological surfaces such as skin can evoke therapeutic responses (11). Such properties also unexpectedly render sound energy suitable for application for the control of sperm motility. Each sperm is only about 50 microns long and 8 microns wide, enabling sound energy to govern, block and/or direct the motility of sperm (12). The male reproductive tract is accessible and receptive to sound energy, and sperm may be managed with sound energy, outside of the male reproductive tract. When used for contraceptive purposes, sound energy disrupts the sperms motility and delays their transit from the testes to the epididymis, where if they are not ejaculated, they die in approximately 74 days (12). Treatment with sound energy renders the sperm immotile and produces an ejaculate containing sperm that cannot fertilize an ovum. It is also likely that the attenuation of an ultrasound signal is due to the conversion of mechanical wave energy to heat. Sperm are produced at temperatures 1-2oC below the core temperature of 37oC and are stored, in effect, outside the body, in the testicles by the spermatic cord. Thus, it is also plausible that any experimental male contraceptive method that heats the testicles where they can no longer produce sperm offers the possibility of a favourable benefit to risk ratio. As regards ultrasound, original research in many species, including studies in humans, have been published. In 2007, one study showed efficacy in rats and dogs. It remains unclear, however, about the duration, as well as reversibility, of the effects. To achieve ultrasound contraception, ultrasound waves, which are very short and inaudible sound waves, are applied to the testes. The waves used are of the same type and intensity as those used by physical therapists to treat injuries; in fact, an appropriate machine is already sitting in chiropractors’ and physical therapists’ offices around the world. In a classic and seminal study of the comparative
9
contraceptive effects of heat, ultrasound, infrared rays, and microwave rays, ultrasound was the safest and most effective (13). Dosage varied by species, but in general, in larger animals, 15 minutes of ultrasound resulted in four to six months of infertility. With two treatments 48 hours apart, six to ten months of infertility can result. Fertility returned gradually once the infertile months were over. Longer and higher doses of ultrasound for permanent sterilization, and ultrasound to treat pain and swelling of the epididymis after vasectomy have also been studied in humans. In one study in rats, ultrasound decreased sperm count. In monkeys, the effect took longer to achieve than in rats. Specifically, three treatments every other day of 30 minutes each produced 6 weeks of a beneficial treatment effect. In dogs, a regimen of three applications of ultrasound at 1 MHz and 1.5 W/cm2 lasting 5 minutes, with an interval of 48 hours, was effective as permanent sterilization. The methods to achieve long-lasting effects in large adult monkeys, and humans, have not yet been elucidated (14). During the procedure, a patient sits in a special chair with his scrotum in a cup of water. In the bottom of the cup is an ultrasound element, which heats the water to the temperature of a hot tub up to 140 degrees F. It has been hypothesized that the ultrasound creates an ion exchange between the fluid in the seminiferous tubules and the rete testis, making the environment in the testes inhospitable for sperm formation. It is also probable that the heat produced when the tissue absorbs the high-pressure sound waves from the ultrasound could have also resulted in sterility. The method is painless and some men even report the procedure to be pleasurable (15). In another study, which did not support the hypothesis, the researcher exposed the animal’s entire hind-end to the ultrasound water bath and, not surprisingly, could not find a power level that was effective without burning the bony, delicate tail structure.
10
In 2009, researchers concluded that “it is now clear, under the right conditions; ultrasound works in dogs and rats and has some effect in monkeys” (16). Nonetheless, even at present, it has not yet been possible to achieve long-lasting effects in large adult monkeys and humans. In addition, Italian researchers utilized three treatments in a row, one every other day, on five dogs (16). When semen analysis was done at 2 weeks, there was no sperm. In a subsequent study in 25 dogs, the treatment was five minutes a day, every other day – and based on the way the testes looked when they removed them at day 20; they concluded permanent contraception from that treatment. Interestingly, the Italian researchers rubbed the transducer around the testes by hand, using ultrasound gel, a technique analogous to physical therapy in humans, rather than using a cup of water. Further, lower frequency waves seem more efficacious in dogs than in monkeys (16).
EMPIRICAL DATA Our first author (RS) collected data to contribute to the formulation of the sound technique hypothesis that select audio frequencies from within the frequency range of 8 Hz to 22 kHz, delivered at a specific intensity, over a specified time period, in a precise manner, method, and sequence, can impact the motility and viability of sperm in a male human ejaculate. He selected samples of semen that had been collected, evaluated and determined “acceptable,” based on World Health Organization (WHO) standards, by the approved IVF laboratory facility, intended for disposal. The samples, in a “natural” state, were individually placed in Petri dish(s) and positioned in individual acoustic chambers, on a designated Sound platform, for treatment. A set of 2 transducers, were positioned and fixed on the platforms, immediately adjacent to the acoustic
11
chambers, directly above and below, but not in direct contact with the Petri dish(s) or the chamber. The platforms were designed to create a “neutral” environment within which to treat the samples, and effectively demonstrate the principle/concept. This was not an attempt to replicate any live, actual and/or clinical condition The primary test indicators were: 1) sample temperature and 2) count percentage of the sperm – in before and after comparison. Following WHO guidelines, he prepared the samples, presented them for treatment, and reported the comparative (before & after) results. Of 11 samples collected and deemed “acceptable” for treatment: Group A = 9 (82%) achieved the primary outcome of 100% immotility; Group B = 1 (9%) achieved an outcome of 90% immotility; and Group C = 1 (9%) achieved an outcome of 80% immotility. These data contributed important and relevant information to the generation of the hypothesis that treatment with acoustic energy is capable of producing sufficient influence on the motility of human sperm so as to support several avenues of discovery including further research & development, improved equipment selection & specifications, delivery systems, protocol design & methodology, and refinements of frequency selection. This technique includes governing sperm motility and movement and the results may range from disrupting or alternatively, enhancing sperm motility. The technique can be used as a contraceptive, disrupting the sperm’s motility and causing spermatozoon that have traveled from the testes and on to the epididymis where they take up residence for approximately 3 weeks to mature. If the sperm is not ejaculated, they remain there to die in approximately 74 days or, if treated, are rendered immotile, producing an ejaculate containing lifeless sperm. It is also plausible that the technique can be used as a method for increasing the likelihood for conception.
12
In such circumstances, the technique may be used by either the man or woman prior to coitus and the motile action of sperm can be stimulated, therein accelerating the sperm’s motile activity and increasing the potential for more sperm to successfully penetrate the ovum. Consequences of the hypothesis A priority for subsequent ultrasound research is the question of whether and if so, how fertility returns after multiple uses of the method. For example, it is unclear whether a man can safely rely on ultrasound for contraception for five or ten years. When a new contraceptive is introduced, it is standard practice to approve it for short-term use and then extend the approval as long-term data when the original study subjects become available, as was done with other new contraceptives. Further government and foundation sponsored research are necessary to fund the investigator-initiated basic, clinical, observational epidemiologic studies and randomized trials necessary to complete the totality of evidence.
DISCUSSION It is plausible, but unproven, to achieve an ultrasound delivery system housed in a wearable system delivering the required dose of sound or ultrasound energy for effective contraception. Such a device would include an acoustically suitable gel pad to assure proper transmission and safe delivery of ultrasound frequencies, an amplification/regulation module, a frequency source/generator, external and targeted directionality and heat dissipation capability, and a wired, wireless or remote controller. Far from an impossible dream, a device with these characteristics can be developed based on the cumulative knowledge from animal and human studies and move quickly to prototype. Approval could take advantage of multiple patent
13
crossovers, the ability to secure and employ commercially available technologies, and initial approval in countries with a favourable regulatory climate for new technologies. The result would be the creation of an effective and safe male contraception system. The available totality of the evidence indicates that sound energy has the potential for male contraception. Using only select sound frequencies in the audible audio range may disrupt the motility of the maturing sperm, impacting their viability and life potential. The capabilities of sound energy for fertility management include reducing or enhancing fertility by controlling aspects of fertility/conception ranging from sterilization and reversible contraception to enhancing the potential for conception. The technique directs sound energy at the spermatozoa and can either inhibit or enhance their motility and/or movement. The continuing rapid growth of the population of the world which doubled during the 20th century, as well as the increasing fertility rate, has contributed to an evolving and increasing emphasis on contraception. While many female contraceptive methods have been developed and marketed, at present, a widely available male contraception has been limited to condoms, which pose logistical challenges, and vasectomy, which is largely irreversible (17). The use of sound and ultrasound to achieve effective and safe male contraception is a promising but an unproven hypothesis. Based on the existing and incomplete totality of evidence, we hypothesize that the combination of sound with a modified ultrasonic technique in a single system will provide a practical delivery method that merges all of the appropriate and prescribed frequencies to have spermicidal qualities that may result in effective and safe male contraception. These include an acoustically suitable pad to assure proper transmission and delivery without concern for injury from the ultrasound frequencies, amplification and regulation module, a frequency source generator, the complementary heat created, external and targeted
14
directionality and various transport methods, such as wired, wireless, or remote. This methodology also offers the ability to move quickly to prototype, multiple patent crossovers, the ability to secure and employ commercially available technologies, and the opportunity for rapid regulatory approval worldwide. These concepts have been explored in basic research in many animal species as well as humans. To achieve an adequate totality of evidence, the test of this hypothesis requires further basic research in humans to clarify the relevant mechanisms, clinical and observational epidemiologic studies to further explore the hypothesis and large-scale randomized trials to detect reliably the most plausible magnitude of benefits of this promising but unproven technology (18). It is plausible that this technology will represent a major breakthrough to combat world population growth. It is also plausible, that, to paraphrase Thomas Huxley, this beautiful hypothesis will be slain by ugly facts (19).
Financial statement We did not receive either financial support or grants associated with the topics discussed in this manuscript.
Conflicts of interest Dr. Sewak, Ms. Teng, and Professor Learman report no disclosures. Professor Hennekens reports that he is funded by the Charles E. Schmidt College of Medicine of Florida Atlantic
15
University. Professor Hennekens also reports that he serves as an independent scientist in an advisory role to investigators and sponsors as Chair or Member of Data and Safety Monitoring Boards for Amgen, AstraZeneca, Bayer, British Heart Foundation, Cadila, Canadian Institutes of Health Research, DalCor, Lilly, Regeneron, and the Wellcome Foundation; to Aralez, Pfizer and its legal counsel, UpToDate and the United States (U.S.) Food and Drug Administration; receives royalties for authorship or editorship of 3 textbooks and as co-inventor on patents for inflammatory markers and cardiovascular disease that are held by Brigham and Women’s Hospital; has an investment management relationship with the West-Bacon Group within SunTrust Investment Services, which has discretionary investment authority and does not own any common or preferred stock in any pharmaceutical or medical device company.
16
References [1] National Research Council. 2014. Can Earth's and Society's Systems Meet the Needs of 10 Billion People? Summary of a Workshop Washington, DC: The National Academies Press. doi: 10.17226/18817. United Nations, Department of Economic and Social Affairs, Population Division 2011. World Population prospects: The 2010 Revision, Highlights, and Advance Tables. Working Paper No. ESA/P/WP. 220 [2] Manivannan B, Bhande SS, Panneerdoss S, Sriram S, Lohiya NK. "Safety evaluation of longterm vas occlusion with styrene maleic anhydride and its non-invasive reversal on accessory reproductive organs in langurs." Asian J Androl. 2005 Jun; 7(2):195-204. Expanding Options for Male Contraception. Planned Parenthood Advocates of Arizona. 2011-08-08. Retrieved 2012-03-28 [3] Male contraception via simultaneous knockout of α1A-adrenoceptors and P2X1-purinoceptors in mice PNAS 2013 110 (51) 20825-20830; published ahead of print December 2, 2013, doi:10.1073/pnas.1318624110 [4] Parsemus Foundation. Parsemusfoundation.org. Retrieved 2012-10-13 [5] University of Virginia Health System. "Milestone reached on path to new form of male contraception: Discovery allows development of drugs to stop sperm from swimming to egg." ScienceDaily. www.sciencedaily.com/releases/2016/04/160412134741.htm (accessed January 01 2017). [6] Institute of Medicine and National Research Council. 1990. Developing New Contraceptives: Obstacles and Opportunities. Washington, DC: The National Academies Press. doi: 10.17226/1450.Indian J Endocrinol Metab. 2012 Nov-Dec; 16(6): 910–917. doi: 10.4103/2230-8210.102991 PMCID: PMC3510960 [7] MaleContraceptives.org surveys 2006-2008 unpublished survey. Glasier A. Acceptability of contraception for men: a review. Contraception 82(5), 453–456 (2010).• In-depth review of the evidence of women's attitudes toward male contraception. Heinemann K, Saad F, Wiesemes M, White S, Heinemann L. Attitudes toward male fertility control: results of a multinational survey on four continents. Hum. Reprod. 20(2), 549–556 (2005). • In-depth analysis of survey data on male attitudes toward using contraception. [8] Male Contraception Initiative.https://www.malecontraceptive.org/international-consortiummale-contraception/ [9] Parsemus Foundation. https://www.parsemusfoundation.org/wpcontent/uploads/2016/03/Male-Contraception-Attitudes-Surveys-and-Research-7-8-16.pdf
17
[10] Benjamin M. Friedrich Max-Planck-Institut fur Physik komplexer Systeme http://www.mpipks-dresden.mpg.de/mp doc/julichergruppe/webseite/Dissertations/Benjamin Friedrich 2009. pdf [11] Siskin B F, Walker J. Therapeutic aspects of electromagnetic fields for soft-tissue healing. In Blank M ed. Electromagnetic fields: Biological interactions and Mechanisms. Advances in Chemistry Series. Vol 250. Washington, DC: American Chemical Society; 1995:277285. [12] Smith, D.J. (2009). "Human sperm accumulation near surfaces: a simulation study" (PDF). Journal of Fluid Mechanics. 621: 295. doi:10.1017/S0022112008004953. Retrieved 20 May 2012. New York Times http://www.nytimes.com/health/guides/disease/infertility-inmen/print.html [13] Male Contraception Information Project http://www.newmalecontraception.org/ultrasound/. Male contraception: history and development. (PMID:24286773) Kogan P, Wald M. Urol. Clin. North Am. [2014] [14] Parsemus Foundation https://www.parsemusfoundation.org/projects/ultrasound/ Therapeutic Ultrasound as a Potential Male Dog Contraceptive: Determination of the Most Effective Application Protocol. (PMID:26134735) Leoci R, Aiudi G, Silvestre F, Lissner EA, Marino F, Lacalandra GM. Reprod. Domest. Anim. [2015]
[15] Fahim MS, Fahim Z, Harman J, Thompson I, Montie J, Hall DG. Fertil Steril. 1977 Aug; 28(8):823-31. Fahim, M.S., Fahim, Z., Der, R., Hall, D.G., Harman, J. Heat in male contraception (hot water 60° C, infrared, microwave, and ultrasound). Contraception. 1975;11:549. [16] BioMed Central, Reproductive Biology and Endocrinology: http://www.eurekalert.org/pub_releases/2012-01/ bc-ss012712.php. http://www.newmalecontraception.org/usound.htm . [17] Guttmacher Institute https://www.guttmacher.org/gpr/2013/03/search-breakthroughsrenewing-support-contraceptive-research-and-development [18] Hennekens CH, DeMets D. 2011. Statistical association and causation: contributions of different types of evidence. 306:1134-1136 19] Huxley TH. Collected Essays of Thomas Huxley: Discourses Biological and Geological Part Eight, 1894, New York: Kessinger Publishing
18
S0306-9877(17)30104-4 http://dx.doi.org/10.1016/j.mehy.2017.06.010 YMEHY 8591
To appear in:
Medical Hypotheses
Received Date: Revised Date: Accepted Date:
29 January 2017 23 May 2017 20 June 2017
Please cite this article as: R. Sewak, B. Teng, L.A. Learman, C.H. Hennekens, MALE CONTRACEPTION: Prospects for Sound and Ultrasound, Medical Hypotheses (2017), doi: http://dx.doi.org/10.1016/j.mehy. 2017.06.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Revised Draft May 23, 2017, for resubmission Medical Hypotheses MALE CONTRACEPTION: Prospects for Sound and Ultrasound Running title: Prospects for Male Contraception Contributors 1. RS, Robert Sewak Sc.D 2. BT, Bettina Teng, BA 3. LAL, Lee A. Learman, MD, PhD 4. CHH, Charles H. Hennekens, MD, DrPH
Department(s) and institution(s) Charles E. Schmidt College of Medicine and Wilkes Honors College, Florida Atlantic University
Corresponding Author: Charles H. Hennekens, MD, DrPH, First Sir Richard Doll Professor & Senior Academic Advisor to the Dean, Charles E. Schmidt College of Medicine, Florida Atlantic University, 2800 S. Ocean Blvd. PHA, Boca Raton, FL 33432, USA Phone: 561-393-8845, Cell: 561-213-9450, Email: [email protected]
Total number of figures: None Total number of photographs: None Source(s) of support: None Presentation at a meeting: None Conflicting Interest: Dr. Sewak, Ms. Teng, and Professor Learman report no disclosures. Professor Hennekens reports that he is funded by the Charles E. Schmidt College of Medicine of Florida Atlantic University. Professor Hennekens also reports that he serves as an independent scientist in an advisory role to investigators and sponsors as Chair or Member of Data and Safety Monitoring Boards for Amgen, AstraZeneca, Bayer, British Heart Foundation, Cadila, Canadian Institutes of Health Research, DalCor, Genzyme, Lilly, Regeneron, and the Wellcome 1
Foundation; to Aralez, Pfizer and their legal counsel; UpToDate and the United States (U.S.) Food and Drug Administration; receives royalties for authorship or editorship of 3 textbooks and as co-inventor on patents for inflammatory markers and cardiovascular disease that are held by Brigham and Women’s Hospital; has an investment management relationship with the WestBacon Group within SunTrust Investment Services, which has discretionary investment authority and does not own any common or preferred stock in any pharmaceutical or medical device company.
Keywords: male contraception, sound, ultrasound, sperm, motility
2
CONTRIBUTOR’S DETAILS
Contribution Details (to be ticked marked as applicable):
Contributor 1 Concepts
x
Design
x
Definition of intellectual content
x
Literature search
x
Contributor 2 Contributor 3 Contributor 4
x
x
x
x
x
x
Clinical studies Experimental studies
x
Data acquisition
x
Data analysis
x
Statistical analysis
x
Manuscript preparation
x
x
x
x
Manuscript editing
x
x
x
x
Manuscript review
x
x
x
x
Guarantor
x
Summary of work done by the contributors: Dr. Sewak conceived of the hypothesis and defined the intellectual content. All authors participated in the design, literature search, manuscript preparation, manuscript editing, and manuscript review. As Professor Hennekens is the corresponding author he will serve as guarantor.
3
ABSTRACT The worldwide human population growth rate, which doubled during the 20th century, as well as the increasing fertility rate, have contributed to an increasing and evolving emphasis on contraception. With respect to female contraceptive methods, many have been developed, marketed, and are widely available. In contrast, male contraception has been limited to condoms, which pose logistical challenges, and vasectomy, which is largely irreversible. The use of sound to achieve effective and safe male contraception is a promising but unproven hypothesis. Based on the existing and incomplete totality of evidence, we hypothesize that the combination of sound with a modified ultrasonic technique in a single system will provide a practical delivery method that merges all of the appropriate and prescribed frequencies to have spermicidal qualities that may result in effective and safe male contraception. It is also plausible that any experimental male contraceptive method that heats the testicles where they can no longer produce sperm offers the possibility of a favourable benefit to risk ratio. The single system combining sound with a modified ultrasonic technique includes an acoustically suitable pad to assure proper transmission and delivery without concern for injury from the ultrasound frequencies, an amplification and regulation module, a frequency source generator, the complementary heat created along with external and targeted directionality, and various transport methods, such as wired, wireless, or remote. This methodology also offers the ability to move quickly to prototype, achieve multiple patent crossovers, secure and employ commercially available technologies, and provide the opportunity for rapid regulatory approval worldwide. These concepts have been explored in basic research in many animal species as well as humans. To achieve an adequate totality of evidence, the test of this hypothesis requires further
4
basic research in humans to clarify the relevant mechanisms, clinical and observational epidemiologic studies to further explore the hypothesis, and large-scale randomized trials to detect the most plausible magnitude of benefits of this promising but unproven technology. It is plausible that this technology will represent a major breakthrough to combat world population growth. It is also plausible, that, to paraphrase Thomas Huxley, this beautiful hypothesis will be slain by ugly facts.
5
INTRODUCTION The worldwide human population growth rate, which doubled during the 20th century, as well as the increasing fertility rate, has contributed to the increasing emphasis on contraception. Population growth rate is highly dependent on the fertility rate and should this trend in continue, the world population may reach 9.3 billion in 2050 and 10.1 billion in 2100 (1), underscoring the importance of safe and effective contraception as an optimal method for population control. At present, the contraceptive choices available in the market are mainly related to women, while men are limited to condoms and vasectomy as methods of contraception. The former has, to some, an unacceptable failure rate and the latter is largely irreversible (6). Although multicultural studies have shown a relatively high acceptance for male contraception among men, with more than three-fourths of men expressing intent to use a contraceptive (7), with most men and women in various studies finding the concept of male contraception to be acceptable, limitations in male contraception are still present mainly due to biological factors. Indeed, prevention can be achieved without severe cessation of estrogen production in women, while in men, reducing spermatogenesis to prevent pregnancy is difficult to achieve without a severe impact on testosterone production (8). Since the advent of condoms and vasectomies in the mid-20th century, clinicians and public health officials have been exploring other options. For example, in 2005, Reversible Inhibition of Sperm Under Guidance (RISUG), a one-time injection which was supposedly both side effect-free and reversible, was introduced. Yet, RISUG did not go beyond testing and never made it to the marketplace (2). In 2013, reports of a pill that would stop the release of sperm by targeting proteins that help launch sperm remained unsuccessful (3). Scientists have worked on other concepts. By the end of 2015, Vasalgel, a scrotal injection that physically blocks the sperm from entering through the vas deferens, was to
6
be introduced, (4) although there are numerous limitations to this approach. By 2016, researchers isolated an enzyme that is only found in sperm that affects its motility, hoping to create a drug that will render the sperm immotile and unable to swim to the egg, which is hypothesized to be free of hormonal side effects (5).
The Hypothesis One novel approach to male contraception through sound remains a promising but unproven hypothesis. Despite an incomplete totality of evidence, the available, albeit limited data, provides support for the hypothesis.
EVALUATION OF THE HYPOTHESIS Background An ideal contraceptive for men should be easily available, inexpensive, reversible, and easy to use, along with minimal side effects and changes in libido. The concept of male contraception is relatively well received across the world. Indeed, most men and women in various multicultural studies find the idea of male contraceptive use to be an acceptable option. An available effective form of male contraception would create more contraceptive options besides hormonal pills, patches, rings, and implants for women, as well as condoms and vasectomies for men.
In discussions about male contraception, about half of men surveyed would be willing to use new male contraceptive methods. This figure varies by country and is often related to demographic variables which include the acceptability of using existing contraceptive options.
7
A daily pill was reported as most acceptable in many locations, followed by implants and injections. In a survey of self-selected participants interested in new male contraceptive options, 99% said they would use a new method, 72% of women said they would trust men to use a new method, and there was a preference for non-hormonal methods given by yearly injection or a daily pill (9). In most surveys, respondents clearly favored a reversible option as opposed to vasectomy.
Sound and Ultrasound to Achieve Male Contraception This novel technique utilizes sound energy in the audible range for management and control of male fertility, using only select sound frequencies to disrupt the motility of the maturing sperm, impacting their viability and life potential. For example, sound can be used to reduce or enhance fertility by controlling aspects of fertility/conception, including sterilization, contraception and enhancing conception potential. The technique directs sound energy at the spermatozoa and can either inhibit or enhance their motility and/or movement (10). The sound energy, the select frequencies, the level of intensity, type of the energy, as well as waveform configuration and treatment duration can be adjusted in relation to the desired outcome. By example, the amount of applied sound energy may be greater for disrupting, blocking and/or disabling sperm, as described; and may be reduced for guiding and/or promoting sperm movement. In either situation, the sound energy may optionally be applied: continuously, in single bursts or, pulsated, in accordance with requirements for both the application and the intended outcome. Sound energy may be viewed as being mechanical in that it consists of the vibration of molecules about their equilibrium positions. Furthermore, it is known and accepted that the
8
application of sound energy on biological surfaces such as skin can evoke therapeutic responses (11). Such properties also unexpectedly render sound energy suitable for application for the control of sperm motility. Each sperm is only about 50 microns long and 8 microns wide, enabling sound energy to govern, block and/or direct the motility of sperm (12). The male reproductive tract is accessible and receptive to sound energy, and sperm may be managed with sound energy, outside of the male reproductive tract. When used for contraceptive purposes, sound energy disrupts the sperms motility and delays their transit from the testes to the epididymis, where if they are not ejaculated, they die in approximately 74 days (12). Treatment with sound energy renders the sperm immotile and produces an ejaculate containing sperm that cannot fertilize an ovum. It is also likely that the attenuation of an ultrasound signal is due to the conversion of mechanical wave energy to heat. Sperm are produced at temperatures 1-2oC below the core temperature of 37oC and are stored, in effect, outside the body, in the testicles by the spermatic cord. Thus, it is also plausible that any experimental male contraceptive method that heats the testicles where they can no longer produce sperm offers the possibility of a favourable benefit to risk ratio. As regards ultrasound, original research in many species, including studies in humans, have been published. In 2007, one study showed efficacy in rats and dogs. It remains unclear, however, about the duration, as well as reversibility, of the effects. To achieve ultrasound contraception, ultrasound waves, which are very short and inaudible sound waves, are applied to the testes. The waves used are of the same type and intensity as those used by physical therapists to treat injuries; in fact, an appropriate machine is already sitting in chiropractors’ and physical therapists’ offices around the world. In a classic and seminal study of the comparative
9
contraceptive effects of heat, ultrasound, infrared rays, and microwave rays, ultrasound was the safest and most effective (13). Dosage varied by species, but in general, in larger animals, 15 minutes of ultrasound resulted in four to six months of infertility. With two treatments 48 hours apart, six to ten months of infertility can result. Fertility returned gradually once the infertile months were over. Longer and higher doses of ultrasound for permanent sterilization, and ultrasound to treat pain and swelling of the epididymis after vasectomy have also been studied in humans. In one study in rats, ultrasound decreased sperm count. In monkeys, the effect took longer to achieve than in rats. Specifically, three treatments every other day of 30 minutes each produced 6 weeks of a beneficial treatment effect. In dogs, a regimen of three applications of ultrasound at 1 MHz and 1.5 W/cm2 lasting 5 minutes, with an interval of 48 hours, was effective as permanent sterilization. The methods to achieve long-lasting effects in large adult monkeys, and humans, have not yet been elucidated (14). During the procedure, a patient sits in a special chair with his scrotum in a cup of water. In the bottom of the cup is an ultrasound element, which heats the water to the temperature of a hot tub up to 140 degrees F. It has been hypothesized that the ultrasound creates an ion exchange between the fluid in the seminiferous tubules and the rete testis, making the environment in the testes inhospitable for sperm formation. It is also probable that the heat produced when the tissue absorbs the high-pressure sound waves from the ultrasound could have also resulted in sterility. The method is painless and some men even report the procedure to be pleasurable (15). In another study, which did not support the hypothesis, the researcher exposed the animal’s entire hind-end to the ultrasound water bath and, not surprisingly, could not find a power level that was effective without burning the bony, delicate tail structure.
10
In 2009, researchers concluded that “it is now clear, under the right conditions; ultrasound works in dogs and rats and has some effect in monkeys” (16). Nonetheless, even at present, it has not yet been possible to achieve long-lasting effects in large adult monkeys and humans. In addition, Italian researchers utilized three treatments in a row, one every other day, on five dogs (16). When semen analysis was done at 2 weeks, there was no sperm. In a subsequent study in 25 dogs, the treatment was five minutes a day, every other day – and based on the way the testes looked when they removed them at day 20; they concluded permanent contraception from that treatment. Interestingly, the Italian researchers rubbed the transducer around the testes by hand, using ultrasound gel, a technique analogous to physical therapy in humans, rather than using a cup of water. Further, lower frequency waves seem more efficacious in dogs than in monkeys (16).
EMPIRICAL DATA Our first author (RS) collected data to contribute to the formulation of the sound technique hypothesis that select audio frequencies from within the frequency range of 8 Hz to 22 kHz, delivered at a specific intensity, over a specified time period, in a precise manner, method, and sequence, can impact the motility and viability of sperm in a male human ejaculate. He selected samples of semen that had been collected, evaluated and determined “acceptable,” based on World Health Organization (WHO) standards, by the approved IVF laboratory facility, intended for disposal. The samples, in a “natural” state, were individually placed in Petri dish(s) and positioned in individual acoustic chambers, on a designated Sound platform, for treatment. A set of 2 transducers, were positioned and fixed on the platforms, immediately adjacent to the acoustic
11
chambers, directly above and below, but not in direct contact with the Petri dish(s) or the chamber. The platforms were designed to create a “neutral” environment within which to treat the samples, and effectively demonstrate the principle/concept. This was not an attempt to replicate any live, actual and/or clinical condition The primary test indicators were: 1) sample temperature and 2) count percentage of the sperm – in before and after comparison. Following WHO guidelines, he prepared the samples, presented them for treatment, and reported the comparative (before & after) results. Of 11 samples collected and deemed “acceptable” for treatment: Group A = 9 (82%) achieved the primary outcome of 100% immotility; Group B = 1 (9%) achieved an outcome of 90% immotility; and Group C = 1 (9%) achieved an outcome of 80% immotility. These data contributed important and relevant information to the generation of the hypothesis that treatment with acoustic energy is capable of producing sufficient influence on the motility of human sperm so as to support several avenues of discovery including further research & development, improved equipment selection & specifications, delivery systems, protocol design & methodology, and refinements of frequency selection. This technique includes governing sperm motility and movement and the results may range from disrupting or alternatively, enhancing sperm motility. The technique can be used as a contraceptive, disrupting the sperm’s motility and causing spermatozoon that have traveled from the testes and on to the epididymis where they take up residence for approximately 3 weeks to mature. If the sperm is not ejaculated, they remain there to die in approximately 74 days or, if treated, are rendered immotile, producing an ejaculate containing lifeless sperm. It is also plausible that the technique can be used as a method for increasing the likelihood for conception.
12
In such circumstances, the technique may be used by either the man or woman prior to coitus and the motile action of sperm can be stimulated, therein accelerating the sperm’s motile activity and increasing the potential for more sperm to successfully penetrate the ovum. Consequences of the hypothesis A priority for subsequent ultrasound research is the question of whether and if so, how fertility returns after multiple uses of the method. For example, it is unclear whether a man can safely rely on ultrasound for contraception for five or ten years. When a new contraceptive is introduced, it is standard practice to approve it for short-term use and then extend the approval as long-term data when the original study subjects become available, as was done with other new contraceptives. Further government and foundation sponsored research are necessary to fund the investigator-initiated basic, clinical, observational epidemiologic studies and randomized trials necessary to complete the totality of evidence.
DISCUSSION It is plausible, but unproven, to achieve an ultrasound delivery system housed in a wearable system delivering the required dose of sound or ultrasound energy for effective contraception. Such a device would include an acoustically suitable gel pad to assure proper transmission and safe delivery of ultrasound frequencies, an amplification/regulation module, a frequency source/generator, external and targeted directionality and heat dissipation capability, and a wired, wireless or remote controller. Far from an impossible dream, a device with these characteristics can be developed based on the cumulative knowledge from animal and human studies and move quickly to prototype. Approval could take advantage of multiple patent
13
crossovers, the ability to secure and employ commercially available technologies, and initial approval in countries with a favourable regulatory climate for new technologies. The result would be the creation of an effective and safe male contraception system. The available totality of the evidence indicates that sound energy has the potential for male contraception. Using only select sound frequencies in the audible audio range may disrupt the motility of the maturing sperm, impacting their viability and life potential. The capabilities of sound energy for fertility management include reducing or enhancing fertility by controlling aspects of fertility/conception ranging from sterilization and reversible contraception to enhancing the potential for conception. The technique directs sound energy at the spermatozoa and can either inhibit or enhance their motility and/or movement. The continuing rapid growth of the population of the world which doubled during the 20th century, as well as the increasing fertility rate, has contributed to an evolving and increasing emphasis on contraception. While many female contraceptive methods have been developed and marketed, at present, a widely available male contraception has been limited to condoms, which pose logistical challenges, and vasectomy, which is largely irreversible (17). The use of sound and ultrasound to achieve effective and safe male contraception is a promising but an unproven hypothesis. Based on the existing and incomplete totality of evidence, we hypothesize that the combination of sound with a modified ultrasonic technique in a single system will provide a practical delivery method that merges all of the appropriate and prescribed frequencies to have spermicidal qualities that may result in effective and safe male contraception. These include an acoustically suitable pad to assure proper transmission and delivery without concern for injury from the ultrasound frequencies, amplification and regulation module, a frequency source generator, the complementary heat created, external and targeted
14
directionality and various transport methods, such as wired, wireless, or remote. This methodology also offers the ability to move quickly to prototype, multiple patent crossovers, the ability to secure and employ commercially available technologies, and the opportunity for rapid regulatory approval worldwide. These concepts have been explored in basic research in many animal species as well as humans. To achieve an adequate totality of evidence, the test of this hypothesis requires further basic research in humans to clarify the relevant mechanisms, clinical and observational epidemiologic studies to further explore the hypothesis and large-scale randomized trials to detect reliably the most plausible magnitude of benefits of this promising but unproven technology (18). It is plausible that this technology will represent a major breakthrough to combat world population growth. It is also plausible, that, to paraphrase Thomas Huxley, this beautiful hypothesis will be slain by ugly facts (19).
Financial statement We did not receive either financial support or grants associated with the topics discussed in this manuscript.
Conflicts of interest Dr. Sewak, Ms. Teng, and Professor Learman report no disclosures. Professor Hennekens reports that he is funded by the Charles E. Schmidt College of Medicine of Florida Atlantic
15
University. Professor Hennekens also reports that he serves as an independent scientist in an advisory role to investigators and sponsors as Chair or Member of Data and Safety Monitoring Boards for Amgen, AstraZeneca, Bayer, British Heart Foundation, Cadila, Canadian Institutes of Health Research, DalCor, Lilly, Regeneron, and the Wellcome Foundation; to Aralez, Pfizer and its legal counsel, UpToDate and the United States (U.S.) Food and Drug Administration; receives royalties for authorship or editorship of 3 textbooks and as co-inventor on patents for inflammatory markers and cardiovascular disease that are held by Brigham and Women’s Hospital; has an investment management relationship with the West-Bacon Group within SunTrust Investment Services, which has discretionary investment authority and does not own any common or preferred stock in any pharmaceutical or medical device company.
16
References [1] National Research Council. 2014. Can Earth's and Society's Systems Meet the Needs of 10 Billion People? Summary of a Workshop Washington, DC: The National Academies Press. doi: 10.17226/18817. United Nations, Department of Economic and Social Affairs, Population Division 2011. World Population prospects: The 2010 Revision, Highlights, and Advance Tables. Working Paper No. ESA/P/WP. 220 [2] Manivannan B, Bhande SS, Panneerdoss S, Sriram S, Lohiya NK. "Safety evaluation of longterm vas occlusion with styrene maleic anhydride and its non-invasive reversal on accessory reproductive organs in langurs." Asian J Androl. 2005 Jun; 7(2):195-204. Expanding Options for Male Contraception. Planned Parenthood Advocates of Arizona. 2011-08-08. Retrieved 2012-03-28 [3] Male contraception via simultaneous knockout of α1A-adrenoceptors and P2X1-purinoceptors in mice PNAS 2013 110 (51) 20825-20830; published ahead of print December 2, 2013, doi:10.1073/pnas.1318624110 [4] Parsemus Foundation. Parsemusfoundation.org. Retrieved 2012-10-13 [5] University of Virginia Health System. "Milestone reached on path to new form of male contraception: Discovery allows development of drugs to stop sperm from swimming to egg." ScienceDaily. www.sciencedaily.com/releases/2016/04/160412134741.htm (accessed January 01 2017). [6] Institute of Medicine and National Research Council. 1990. Developing New Contraceptives: Obstacles and Opportunities. Washington, DC: The National Academies Press. doi: 10.17226/1450.Indian J Endocrinol Metab. 2012 Nov-Dec; 16(6): 910–917. doi: 10.4103/2230-8210.102991 PMCID: PMC3510960 [7] MaleContraceptives.org surveys 2006-2008 unpublished survey. Glasier A. Acceptability of contraception for men: a review. Contraception 82(5), 453–456 (2010).• In-depth review of the evidence of women's attitudes toward male contraception. Heinemann K, Saad F, Wiesemes M, White S, Heinemann L. Attitudes toward male fertility control: results of a multinational survey on four continents. Hum. Reprod. 20(2), 549–556 (2005). • In-depth analysis of survey data on male attitudes toward using contraception. [8] Male Contraception Initiative.https://www.malecontraceptive.org/international-consortiummale-contraception/ [9] Parsemus Foundation. https://www.parsemusfoundation.org/wpcontent/uploads/2016/03/Male-Contraception-Attitudes-Surveys-and-Research-7-8-16.pdf
17
[10] Benjamin M. Friedrich Max-Planck-Institut fur Physik komplexer Systeme http://www.mpipks-dresden.mpg.de/mp doc/julichergruppe/webseite/Dissertations/Benjamin Friedrich 2009. pdf [11] Siskin B F, Walker J. Therapeutic aspects of electromagnetic fields for soft-tissue healing. In Blank M ed. Electromagnetic fields: Biological interactions and Mechanisms. Advances in Chemistry Series. Vol 250. Washington, DC: American Chemical Society; 1995:277285. [12] Smith, D.J. (2009). "Human sperm accumulation near surfaces: a simulation study" (PDF). Journal of Fluid Mechanics. 621: 295. doi:10.1017/S0022112008004953. Retrieved 20 May 2012. New York Times http://www.nytimes.com/health/guides/disease/infertility-inmen/print.html [13] Male Contraception Information Project http://www.newmalecontraception.org/ultrasound/. Male contraception: history and development. (PMID:24286773) Kogan P, Wald M. Urol. Clin. North Am. [2014] [14] Parsemus Foundation https://www.parsemusfoundation.org/projects/ultrasound/ Therapeutic Ultrasound as a Potential Male Dog Contraceptive: Determination of the Most Effective Application Protocol. (PMID:26134735) Leoci R, Aiudi G, Silvestre F, Lissner EA, Marino F, Lacalandra GM. Reprod. Domest. Anim. [2015]
[15] Fahim MS, Fahim Z, Harman J, Thompson I, Montie J, Hall DG. Fertil Steril. 1977 Aug; 28(8):823-31. Fahim, M.S., Fahim, Z., Der, R., Hall, D.G., Harman, J. Heat in male contraception (hot water 60° C, infrared, microwave, and ultrasound). Contraception. 1975;11:549. [16] BioMed Central, Reproductive Biology and Endocrinology: http://www.eurekalert.org/pub_releases/2012-01/ bc-ss012712.php. http://www.newmalecontraception.org/usound.htm . [17] Guttmacher Institute https://www.guttmacher.org/gpr/2013/03/search-breakthroughsrenewing-support-contraceptive-research-and-development [18] Hennekens CH, DeMets D. 2011. Statistical association and causation: contributions of different types of evidence. 306:1134-1136 19] Huxley TH. Collected Essays of Thomas Huxley: Discourses Biological and Geological Part Eight, 1894, New York: Kessinger Publishing
18