MALE CONTRACEPTION UPDATE

Summaries of new peer-reviewed publications

Epididymal targets
Identifies epithelial cadherin mRNA in the caput, corpus and cauda epididymis epithelium.  Four E-cadherin forms are also identified on the surface of pre- and post-acrosome reaction sperm.  Incubation of sperm with antibodies to E-cadherin results in both reduced zona pellucida binding and reduced ZP-free oocyte binding. 
Expression of Epithelial Cadherin in the Human Male Reproductive Tract and Gametes and Evidence of its Participation in Fertilization.
Marín-Briggiler CI, Veiga MF, Matos ML, González Echeverría MF, Furlong LI, Vazquez-Levin MH.
Mol Hum Reprod. 2008 Oct 1. [Epub ahead of print]
PMID: 18829448

Gamete binding / fusion targets
Cysteine-RIch Secretory Proteins (CRISPs) regulate ion channel activity.  While they are abundant in the mammalian reproductive tracts, they are also found in “secretory epithelia of exocrine glands, and immune tissues including the spleen and thymus” of mice, indicating a wider role.
Cysteine-rich secretory proteins are not exclusively expressed in the male reproductive tract.
Reddy T, Gibbs GM, Merriner DJ, Kerr JB, O'Bryan MK.
Dev Dyn. 2008 Oct 15;237(11):3313-3323. [Epub ahead of print]
PMID: 18924239

Immunological approaches
Further information on the human sperm surface protein, eppin, and the contraceptive mechanism of action of an induced anti-eppin immune response. Eppin antibodies decreased human sperm progressive motility and suppressed cAMP utilization.  Eppin antibodies from infertile monkeys prevented semenogelin binding to eppin, impeding “liquefaction and the initiation of progressive motility.”
Inhibition of Human Sperm Motility by Contraceptive Anti-Eppin Antibodies from Infertile Male Monkeys: Effect on Cyclic Adenosine Monophosphate.
O'Rand MG, Widgren EE, Beyler S, Richardson RT.
Biol Reprod. 2008 Oct 22. [Epub ahead of print]
PMID: 18945989

Semen analysis standardization
A non-comparative observational study of SpermCheck Vasectomy’s accuracy and ease of use.  “The positive predictive value of the test was 93% (79% to 98%), and most importantly the negative predictive value was 97% (91% to 99%). The test gave a positive result 100% of the time at sperm concentrations of 385,000/ml or greater.”  Lay volunteers found the test easy to use and the instructions understandable.
Clinical and Consumer Trial Performance of a Sensitive Immunodiagnostic Home Test That Qualitatively Detects Low Concentrations of Sperm Following Vasectomy.
Klotz KL, Coppola MA, Labrecque M, Brugh VM 3rd, Ramsey K, Kim KA, Conaway MR, Howards SS, Flickinger CJ, Herr JC.
J Urol. 2008 Oct 17. [Epub ahead of print]
PMID: 18930494

The universality of the World Health Organization semen parameters is uncertain.  This study analyzed semen samples from 105 healthy and demonstrably fertile Chinese men. They found that the “values of semen parameters for Chinese men are lower than the WHO criteria, especially for rapid progressive motility [average 79% lower], progressive motility [52% lower], and sperm viability [46% lower], and a different standard for Chinese may be needed.”
Reference values of semen parameters for healthy Chinese men.
Gao J, Gao ES, Walker M, Yang Q, Wu JQ, Zhu QX, Wen SW.
Urol Int. 2008;81(3):256-62.
PMID: 18931539

Endocrinological approaches
Further information on the mechanism of action of hormonal treatment combined with hyperthermia in monkeys.  While endothelial nitric oxide synthase (eNOS) levels did not change in the treatment versus control groups, “treatment of heat or heat in combination with T markedly induced iNOS expression in germ cells,” suggesting a role for inducible NOS in “testicular germ cell death after heat and/or T treatment.”
Expression of Nitric Oxide Synthase During Germ Cell Apoptosis in Testis of Cynomolgus Monkey after Testosterone and Heat Treatment.
Guo J, Jia Y, Tao S, Li Y, Zhang X, Hu Z, Chiang N, Lue YH, Hikim AP, Swerdloff RS, Wang C, Liu Y.
J Androl. 2008 Oct 2. [Epub ahead of print]
PMID: 18835830

Endocrinological supporting research
In a study of 2,878 men age 40 and over in 8 European countries, “CAG repeat polymorphism in exon 1 of the androgen receptor (AR)” was positively associated with “total, free and bioavailable levels of testosterone (T) and estradiol (E2). FSH but not LH correlated inversely with CAG repeat length… Weaker transcriptional activity of the AR with longer CAG-encoded polyglutamine repeats appears to be totally or near-totally compensated for by higher T levels” in these aging men.  This study echoes findings that CAG-repeat length is unassociated with non-response to male hormonal contraceptive regimens. 
Increased Estrogen Rather Than Decreased Androgen Action Is Associated with Longer Androgen Receptor CAG Repeats.
Huhtaniemi IT, Pye SR, Limer KL, Thomson W, O'Neill TW, Platt H, Payne D, John SL, Jiang M, Boonen S, Borghs H, Vanderschueren D, Adams JE, Ward KA, Bartfai G, Casanueva F, Finn JD, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Silman AJ, Wu FC; the EMAS study group.
J Clin Endocrinol Metab. 2008 Oct 7. [Epub ahead of print]
PMID: 18840639

A study of Epididymal cellular structure after orchidectomy and following testosterone replacement. “We found that BrdU-incorporation and PCNA expression increased significantly 3 days after testosterone replacement in all regions of the regressed epididymis except in the initial segment. The highest mitotic activity was seen in the corpus epididymidis at 3-day post-implantation. Using specific markers for each cell type, we found no significant changes in the proportion of each cell type compared to control,… [demonstrating] that the mammalian epididymis is not a static tissue without any significant cell renewal.”
Effect of Testosterone on Epithelial Cell Proliferation in the Regressed Rat Epididymis.
Hamzeh M, Robaire B.
J Androl. 2008 Oct 16.
PMID: 18930902

Hypoxia inducible factor (HIF)-1alpha may have a role in regulating Leydig cell function.  “Because of its vascular arrangement and the high metabolic demand of spermatogenesis the testis has previously been described as functioning on the brink of hypoxia.”  Western blot and immunohistochemistry localize HIF-1alpha to interstitial Leydig cells. “[The] promoter of the mouse 3beta hydroxysteroid dehydrogenase type I (Hsd3b1) gene, which encodes a key enzyme in testosterone production, is a potential target of HIF-1alpha.”
Hypoxia Inducible Factor-1alpha Is Constitutively Expressed in Murine Leydig Cells and Regulates 3beta-Hydroxysteroid Dehydrogenase Type I Promoter Activity.
Lysiak JJ, Kirby JL, Tremblay JJ, Woodson RI, Reardon MA, Palmer LA, Turner TT.
J Androl. 2008 Oct 16.
PMID: 18930903

A summary of the findings of a special issue devoted to the “physiologic roles and putative pharmacological implications of kisspeptins in the control of male and female gonadotropic axis.”  This system is amenable to pharmacological control, and “protocols of chronic subcutaneous administration of kisspeptin to male rats have been reported to down-regulate the gonadotropic axis, with extinguished LH responses within 48 h and testicular atrophy.”
Kisspeptins and the control of gonadotropin secretion in male and female rodents.
Roa J, Castellano JM, Navarro VM, Handelsman DJ, Pinilla L, Tena-Sempere M.
Peptides. 2008 Aug 22.
PMID: 18793689

Proteomic / genomic supporting research
Report of a putative cAMP-mediated activation mechanism for a GTPase, Rap1, in sperm.  Rap1 “inactivation in haploid cells leads to a premature release of spermatids from the supporting Sertoli cell resulting in male infertility.”
cAMP-Epac2-mediated activation of Rap1 in developing male germ cells: RA-RhoGAP as a possible direct down-stream effector.
Aivatiadou E, Ripolone M, Brunetti F, Berruti G.
Mol Reprod Dev. 2008 Oct 20. [Epub ahead of print]
PMID: 18937323

Confirmation that sperm failing to initiate post-ICSI egg activation lack PLC, zeta 1 (PLCZ1), “the sperm protein thought to induce [Ca2+](i) oscillations.”  No conclusive gene mutations for abnormal PLCZ1 expression were identified.
Human sperm devoid of PLC, zeta 1 fail to induce Ca release and are unable to initiate the first step of embryo development.
Yoon SY, Jellerette T, Salicioni AM, Lee HC, Yoo MS, Coward K, Parrington J, Grow D, Cibelli JB, Visconti PE, Mager J, Fissore RA.
J Clin Invest. 2008 Oct 16. [Epub ahead of print]
PMID: 18924610

Murine sperm use several routes to regulate their volume when they encounter the hypo-osmotic environment of the female reproductive tract.  Three aquaporin mRNAs have been identified in murine spermatozoa; Western blot confirmed only AQP7 and 8.  The sperm of AQP7 null mice had efficient water transport due to up-regulation of Aqp8 expression.  AQP8 “is a likely candidate for a water channel responsible for physiological sperm volume regulation crucial to in vivo fertilization.”
Aquaporin Isoforms Involved in Physiological Volume Regulation of Murine Spermatozoa.
Yeung CH, Callies C, Rojek A, Nielsen S, Cooper TG.
Biol Reprod. 2008 Oct 1. [Epub ahead of print]
PMID: 18829704

“Znf230, the mouse homologue of the human spermatogenesis-related gene, ZNF230,… is primarily expressed in the nuclei of spermatogonia and subsequently in the acrosome system and the entire tail of developing spermatids and spermatozoa. The results indicate that Znf230 may play an important role in mouse spermatogenesis, including spermatogenic cell proliferation and sperm maturation, as well as motility and fertilization.”
Expression and localization of the spermatogenesis-related gene, Znf230, in mouse testis and spermatozoa during postnatal development.
Song H, Su D, Lu P, Yang J, Zhang W, Yang Y, Liu Y, Zhang S.
BMB Rep. 2008 Sep 30;41(9):664-9.
PMID: 18823591

In tumor necrosis factor alpha (TNF-alpha) null mice, testicular tissue shows high levels of Mullerian inhibiting substance (MIS) and have decreased steroidogenesis compared to wild-type.  This study hypothesizes that increased MIS expression is the mechanism of reduced testicular steroidogenesis in TNA-alpha knockout mice.
Reduced testicular steroidogenesis in tumor necrosis factor-alpha knockout mice.
Suh JH, Gong EY, Hong CY, Park E, Ahn RS, Park KS, Lee K.
J Steroid Biochem Mol Biol. 2008 Sep 11.
PMID: 18832037

Adhesion target supporting research
“This article introduces the structure and function of the Sertoli cell cytoskeleton of the testis and the research progress in this aspect, focusing on the description of the function of vimentin, with some illustrations on the impact of physical and chemical factors on cytoskeleton, especially the structural changes of vimentin cell microfilament under simulated microgravity and space true microgravity.
Zhonghua Nan Ke Xue. 2008 Aug;14(8):675-9.
Progress in the research of Sertoli cell cytoskeleton of the testis. [Chinese]
Cao XW.
PMID: 18817336

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Research in China

The Chinese government has long supported male contraception research, and the Chinese "No-Scalpel Vasectomy" procedure is now recognized as the worldwide gold standard.  This month we update you on potential non-permanent methods. Thanks to Dr. Yi-Qun Gu, of China’s National Research Institute for Family Planning, and Dr. Kirsten Vogelsong, of the World Health Organization, for providing this information!

Endocrinological approaches
Testosterone-only approaches have proven quite effective in Asian men, while a testosterone plus progestin regime is now standard for studies in Caucasian men. Results from the China/WHO collaboration on testosterone undecanoate (TU)-only male contraception will soon be published. Recruitment ran December 2001 - December 2002; a total of 1045 subjects from 10 participating centers in China were recruited and administered intramuscular depot TU injections. All data collection has now been completed and the manuscript is under revision. Another paper from this sudy's data was published earlier this year regarding androgen receptor gene polymorphisms' relationship to non-suppression of spermatogenesis (Li JW, Gu YQ, Asian J Androl, 2008 10(5): 723-30).

Chinese design of the Intra Vas Device (IVD)
A phase II clinical trial of the Chinese IVD design, sponsored by the State Family Planning Committee, is going well. The Chinese IVD is a flexible urethane tube filled with a medical-grade nylon mesh that acts as a sieve to capture sperm. One device is implanted in each vas deferens, and a small hole allows the fluid in the vasa deferentia to pass while the sperm stay trapped or pass through in pieces.  The intent of the design is to reduce vassal fluid pressure on the epididymis and increase reversibility. The trial includes IVD insertion and follow-up at 3 months, 1 year and 2 years. The principal investigators are Dr. Zhen-Wen Chen and Dr. Yi-Qun Gu. A total of 1516 Chinese men were recruited from 4 centers in China. Measured outcomes include efficacy (via sperm count and pregnancy rate), safety (short- and long-term complications), patency of vas deferens (via neutral α-glucodase activity) and potential reversibility (via serum antisperm antibodies). One year results were published in the International Journal of Andrology in 2006; they showed that the IVD was slightly less effective than no-scalpel vasectomy (94% vs. 98-99%), but had fewer adverse events. Two-year clinical follow-up has now been completed and the data are being assembled for statistical analysis.  We look forward to the results, and to hearing whether the earlier 94% success rate based on semen analysis was enough to prevent pregnancies for the full 2 years.

Trypterygium wilfordii
Extracts of this herb, commonly used in Chinese medicine, have been shown to produce reversible infertility in men.  Because the herb extract is effective against autoimmune diseases at 3 times the contraceptive dose, the World Health Organization collaborated on analysis of purified derivatives to see whether one might be free of anti-immune activity.  This work foundered when the first of the derivatives, triptolide, didn't work out and money ran short.  No funds are immediately forthcoming to re-start the time-consuming process of testing the other 5 active compounds.  Meanwhile, this known contraceptive herb is commercially available in pill form, but should only be used by men with autoimmune conditions (such as psoriasis and arthritis) until larger studies determine whether the small contraceptive dose is free of immune effects, as it appears to be.  Research could answer that question, but further research in China has been stymied by the much stricter recent drug regulations.  The regulatory changes require that any clinical research on drugs, even on already-existing products or a change of indication, must be approved by the drug regulatory agency. Previously, such clinical research needed only to be approved by the ethics committee in the hospital or institution.

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The public health rationale for new male contraceptives

An October supplement to the journal Contraception publishes the proceedings of the final Application of Molecular Pharmacology to Post-Meiotic Activity (AMPPA-II) meeting.  The articles report on progress in research and position the development of new contraceptives in an international public health framework. 

Dr. Jacqui Darroch – formerly of the Guttmacher Institute and the Gates Foundation – spoke about male contraceptive development from an international public health perspective.  She summarized a wealth of data from developing countries using 40 years of Demographic and Health Survey results.  She showed that the average desired family size of men and women around the world has dropped.  While contraceptive use has increased in the last decades, unmet need for contraception remained persistent.  With population size growing, demand for reliable family planning options will only continue to rise.  Finally, dissatisfaction with current methods and fear of side effects have grown consistently as a reason for non-use.  All of these observations support the need for new family planning options

• “Men have a stake in fertility control; they have a long history of contraceptive use, but, with the development of effective female-used methods, most of method use has been passed to women, relieving men and/or pushing them out from the sphere of contraception. Development of new methods for men can change this.
• "Patterns of contraceptive use vary widely, by personal, relationship, service setting and cultural contexts. New methods for men are likely to be integrated into lifetime patterns of male- and female-used methods rather than substitute entirely for female-used methods.
• "Most contraceptive users, and most unmet need, exist in developing countries. Potential opportunities—and needs—for improved use exist among nonusers, users of traditional methods, as well as current users of male and of female methods. Dissatisfaction with currently used methods also indicates opportunities for introduction of new male methods into developed countries such as the United States.
• "Markets for new male methods will need to be activated, rather than be expected to respond to active demand as was the case when modern female-used methods were introduced in the early 1960s.
• "Motivating factors for use of new male methods are most likely to be dissatisfaction with current method options and partner encouragement or interest.
• "Problems evident in female contraceptive use are likely also to exist for male methods, including fears about health and other side effects and access problems, such as cost to users and to public funders.
• "The female-focused service system may not be easy to expand to serving males.”

Read more:
Male Fertility Control -- Where are We?
Contraception 78(4 Supp)
Edited by Michael J. Harper

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Huge grant available for nonsurgical (pet) sterilization

What would it take to produce a nonsurgical sterilant for animals? A wealthy inventor, who is also a retired surgeon, is hoping the answer is "a $75 million prize."

Animal-lover Gary Michelson has pledged $25 million to the person or group that comes up with a safe, one-time non-surgical means to sterilize male and female cats, and will devote up to $50 million more to support research on plausible approaches.

We are waiting to hear back on whether the foundation is looking for male sterilants despite the existence of EsterilSol, a zinc gluconate with L-arginine testicular injection developed by the late Dr. Mostafa Fahim of the University of Missouri-Columbia School of Medicine.  This sterilant was once marketed in the US as Neutersol and is expected to return in late 2009 produced by a new partner, Abbott Animal Health.  Neutersol reduces testosterone levels (although less when used in adult animals than in puppies), so is not appropriate for use as a nonsurgical sterilant in humans.

Researchers studying nonsurgical, potentially permanent contraceptives such as l-CDB-4022, RISUG (if it can be performed percutaneously), high-intensity focused ultrasound (HIFU), and immune approaches might consider applying for the funds. "'We're completely agnostic regarding the approach,' says foundation executive director Aimee Gilbreath. 'We'll consider anything. We really believe if cutting-edge technologies are applied we can solve this.'"

Read more:
Inventor Michelson offers $75M for a way to sterilize pets
Humanitarian Offers $75 Million for Single Dose Sterilization of Cats and Dogs

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Press coverage

The University of Calgary student paper covers hormonal clinical trials at the University of Washington. "Clinical testing at the University of Washington shows that the success rate of male hormonal contraceptives can be as high as 100 per cent, with subject's test results showing a sperm count of zero, but this is only if the treatments have any impact. These studies also reveal that 10-15 per cent of males do not respond to treatment, which is a high percentage... A survey by the Kaiser Family Foundation in the U.S. found that 71 per cent of American men would consider an alternative form of birth control and 66 per cent of those surveyed said they would try the male pill... Those in monogamous relationships with sensitivities to condoms or for those women who can't take the pill this is a great alternative... Until there is a higher success rate and a greater demand, we may be waiting longer than once thought for this new and innovative product."

Dudes on the pill: The coming of male birth control
University of Calgary Gauntlet, 23 October

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Calendar of events

 

Planning to attend a male contraception or andrology-related event that's not listed here? Let us know so we can post it and alert your colleagues to interesting upcoming events.

November 8-12	American Society for Reproductive Medicine 64th Annual Meeting; San Francisco, CA, USA
November 24	Deadline for European Congress of Endocrinology abstract submission
November 26-28	5th European Congress of Andrology; Rome, Italy
December 1	Deadline for North American Testis Workshop abstract submission
December 4-6	Second Congress of the Asia-Pacific Council on Contraception (APCOC); Macao, China
December 15	Deadline for World Congress on Reproduction abstract submission
2009
March 5-8	13th World Congress on Human Reproduction; Venice, Italy
March 7-10	9th International Congress on Andrology; Barcelona, Spain
April 1-4	20th North American Testis Workshop; Philadelphia, PA, USA
April 4-7	34th American Society of Andrology meeting; Philadelphia, PA, USA
April 25-29	11th European Congress of Endocrinology; Istanbul, Turkey
May 31	Deadline for Asia-Pacific Forum on Andrology abstract submission
October 10-13	Third Asia-Pacific Forum on Andrology; Nanjing, China

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Editors

Kirsten Thompson, Director of the Male Contraception Coalition (MCC)
Email: Kirsten@MaleContraceptives.org
Phone: +1 (443) 858-1183

Elaine Lissner, Director of the Male Contraception Information Project (MCIP)
Email: Lissner@NewMaleContraception.org
Phone: +1 (415) 839-6304