MALE CONTRACEPTION UPDATE

New peer-reviewed publications

Motility targets
“Promising sperm motility targets include transmembrane calcium channels, a unique adenylyl cyclase, and novel flagellar proteins.”
Inhibiting sperm motility for male contraception: will the sperm tail be its "achilles heel"?
Amory JK.
Mol Interv. 2007 Apr;7(2):68-70.
PMID: 17468385

“Here, we show that alkalinization also has a dramatic effect on membrane potential, producing a rapid hyperpolarization. This hyperpolarization is primarily mediated by a weakly outwardly rectifying K(+) current (I(KSper)) originating from the principal piece of the sperm flagellum. Alkalinization activates the pH(i)-sensitive I(KSper), setting the membrane potential to negative potentials where Ca(2+) entry via I(CatSper) is maximized.”
KSper, a pH-sensitive K+ current that controls sperm membrane potential.
Navarro B, Kirichok Y, Clapham DE.
Proc Natl Acad Sci U S A. 2007 Apr 25; [Epub ahead of print]
PMID: 17460039

Table summarizing TRP channels, known activators, inhibitors, putative interacting proteins and their proposed functions.
SnapShot: mammalian TRP channels.
Clapham DE.
Cell. 2007 Apr 6;129(1):220. No abstract available.
PMID: 17418797

“These results show for the first time that the NK1, NK2 and NK3 tachykinin receptor proteins are present in human spermatozoa. Our findings suggest that tachykinins, probably acting through these three tachykinin receptors, play a role in the regulation of human sperm motility.”
A role for tachykinins in the regulation of human sperm motility.
Ravina CG, Seda M, Pinto FM, Orea A, Fernández-Sánchez M, Pintado CO, Luz Candenas M.
Hum. Reprod. 2007 Apr 16; [Epub ahead of print]
doi:10.1093/humrep/dem069

Cell adhesion targets
Although lonidamine itself is not a contraceptive lead, findings regarding the mechanism of its contraceptive effect may be of interest in relation to other cell adhesion target drugs. This report confirms lonidamine’s triggering of germ cell exfoliation. Also reports on seminiferous tubule and Sertoli cell morphology damage.
Lonidamine affects testicular steroid hormones in immature mice.
Traina ME, Guarino M, Natoli A, Romeo A, Urbani E.
Toxicol Appl Pharmacol. 2007 Apr 17; [Epub ahead of print]
PMID: 17442358

“In this report, C-type natriuretic peptide (CNP) was shown to be a regulator of blood-testis barrier dynamics. Although Sertoli and germ cells contributed to the pool of CNP in the seminiferous epithelium, its receptor, natriuretic peptide receptor B, resided almost exclusively in Sertoli cells.”
C-type natriuretic peptide regulates blood-testis barrier dynamics in adult rat testes.
Xia W, Mruk DD, Cheng CY.
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3841-6. Epub 2007 Feb 27.
PMID: 17360440

Indenopyridines
“[The] antispermatogenic activity of CDB-4022 appears to be a consequence of direct effects on both Sertoli and germ cells.”
Acute Adverse Effects of the Indenopyridine, CDB-4022, on the Ultrastructure of Sertoli Cells, Spermatocytes and Spermatids in Rat Testes: Comparison to the Known Sertoli Cell Toxicant, Di-n-pentylphthalate (DPP).
Hild SA, Reel JR, Dykstra MJ, Mann PC, Marshall GR.
J Androl. 2007 Apr 4; [Epub ahead of print]
PMID: 17409460

Endocrinological approaches
“Serum 17OH-P is a surrogate biomarker of intratesticular testosterone and may be useful in research” on male hormonal contraceptive non-responders.
Serum 17-hydroxyprogesterone strongly correlates with intratesticular testosterone in gonadotropin-suppressed normal men receiving various dosages of human chorionic gonadotropin.
Amory JK, Coviello AD, Page ST, Anawalt BD, Matsumoto AM, Bremner WJ.
Fertil Steril. 2007 Apr 25; [Epub ahead of print]
PMID: 17462643

“Subjects with 2 MENT implants showed peak MENT levels at 4 wk with testosterone concentrations 2nmol/L. Sperm concentrations fell rapidly to <1x106/ml at 12 wk in 8/10 subjects in the MENT group and 13/16 subjects in the testosterone group with equally suppressed gonadotropins. Thereafter suppression was not maintained in the MENT group and 6 men noted loss of libido… These data indicate the importance of the doses of progestogen and testosterone for optimum spermatogenic suppression while minimising side effects.”
7{alpha}-methyl-19-nortestosterone (MENT) vs. testosterone in combination with etonogestrel implants for spermatogenic suppression in normal men.
Walton MJ, Kumar N, Baird DT, Ludow H, Anderson RA.
J Androl. 2007 Apr 25; [Epub ahead of print]
PMID: 17460095

Cochrane review of male hormonal contraception. Conclusion: “No male hormonal contraceptive is ready for clinical use. Most trials were small exploratory studies. As a result, their power to detect important differences was limited and their results imprecise. In addition, the definition of oligozoospermia has been imprecise or inconsistent.To avoid bias, future trials need more attention to the methodological requirements for randomized controlled trials. More trials with adequate power would also be helpful.”
Steroid hormones for contraception in men.
Grimes D, Lopez L, Gallo M, Halpern V, Nanda K, Schulz K.
Cochrane Database Syst Rev. 2007 Apr 18;2:CD004316.
PMID: 17443545

Genomic/proteomic supporting research
“SPANX-N proteins are localized in post-meiotic spermatids exclusively, like SPANX-A/D. But in contrast to SPANX-A/D, SPANX-N are found in all ejaculated spermatozoa rather than only in a subpopulation, are localized in the acrosome rather than in the nuclear envelope, and are expressed at a low level in several nongametogenic adult tissues as well as many cancers.”
Evolutionary Diversification of SPANX-N Sperm Protein Gene Structure and Expression.
Kouprina N, Noskov VN, Pavlicek A, Collins NK, Schoppee Bortz PD, Ottolenghi C, Loukinov D, Goldsmith P, Risinger JI, Kim JH, Westbrook VA, Solomon G, Sounders H, Herr JC, Jurka J, Lobanenkov V, Schlessinger D, Larionov V.
PLoS ONE. 2007 Apr 4;2:e359.
PMID: 17406683

Further evidence of the importance of mouse strain selection for preclinical male contraceptive research.
Mice lacking cyclin-dependent kinase inhibitor p19(Ink4d) show strain-specific effects on male reproduction.
Buchold GM, Magyar PL, O'brien DA.
Mol Reprod Dev. 2007 Mar 28; [Epub ahead of print]
PMID: 17393423

“Epididymal Bfk expression was regulated both by androgens and other testicular factors. It is thus one of the few initial segment enriched genes under androgen control, the majority of them being regulated by other testicular factors.”
Bfk, a novel member of the Bcl2 gene family, is highly expressed in principal cells of the mouse epididymis, and demonstrates a predominant nuclear localization.
Pujianto DA, Damdimopoulos AE, Sipila P, Jalkanen J, Huhtaniemi I, Poutanen M.
Endocrinology. 2007 Apr 5; [Epub ahead of print]
PMID: 17412810

“We propose the term radial spoke protein 44 as an accurate designation, preferable to human meichroacidin because it denotes the restricted localization of the protein to the radial spokes of the axonemes of both sperm and cilia. Further, since the human gene is expressed in brain, thyroid, trachea and lung in addition to testis, we suggest that the gene name be changed from TSGA2 [testis specific gene A2] to radial spoke protein 44 [RSP44].”
Radial spoke protein 44 (human meichroacidin) is an axonemal alloantigen of sperm and cilia.
Shetty J, Klotz KL, Wolkowicz MJ, Flickinger CJ, Herr JC.
Gene. 2007 Mar 23; [Epub ahead of print]
PMID: 17451891

Binding targets
“Our findings suggest that the association with ADAM2 is a key element for stability of ADAM3 in [epididymal] sperm. The presence of the ADAM2/ADAM3 complex in sperm also suggests a potential role of ADAM2 with ADAM3 in sperm binding to the egg zona pellucida.”
Identification of an ADAM2/ADAM3 complex on the surface of mouse testicular germ cells and cauda epididymal sperm.
Nishimura H, Myles DG, Primakoff P.
J Biol Chem. 2007 Apr 17; [Epub ahead of print]
PMID: 17439939

“These exquisitely cell- and species-specific recognition events are among the most strategically important cellular interactions in biology. Understanding the cellular and molecular mechanisms that underpin them has implications for diagnosis of the aetiology of human infertility and the development of novel targets for fertility regulation. Herein, we describe two models indicating the plethora of highly orchestrated molecular interactions underlying successful sperm zona binding and sperm oocyte fusion.”
New insights into the molecular mechanisms of sperm-egg interaction.
Nixon B, Aitken RJ, McLaughlin EA.
Cell Mol Life Sci. 2007 Apr 20; [Epub ahead of print]
PMID: 17447007

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Cochrane Collaboration findings on vasectomy best practices

The Cochrane Collaboration has released a report which clarifies the discrepancies in findings about no-scalpel vasectomy (NSV). The review concludes that no-scalpel vasectomy is indeed a superior technique to traditional vasectomy: less bleeding, hematoma, infection, and pain as well as a shorter operation time. This confirms the findings of studies and reviews by researchers such as Michel Labrecque, David Sokal, and Mark Barone.

However, this conclusion comes with an important caveat: experienced NSV doctors had significantly better results than those who had just been trained, and NSV may be no better than traditional vasectomy in the hands of an inexperienced provider. In one study in which clinians performed a few NSVs after an instructional video and only one supervised procedure, those NSVs had the same rates of complication one would expect from traditional vasectomies.

These results underscore the important role of training (provided by organizations such as EngenderHealth) and experience. Dr. Marc Goldstein, executive director of the Men's Service Center at Cornell University’s Weill Medical College, says men are now requesting NSVs specifically, and he advises them to ask their doctors how much experience they have with the technique. The best doctors have each performed thousands of NSV procedures.

These results also have important implications for family planning managers. In order to decrease the rates of complication with vasectomy, health care managers should concentrate on training a few, highly specialized NSV providers. For vasectomy, “factory medicine” appears to be the best approach.

Read more:
No-scalpel vasectomies by skilled surgeons may speed recovery, April 17
Scalpel versus no-scalpel incision for vasectomy, Cochrane Database Systems Review, April 18

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Leaders of international reproductive health funding organizations under fire

Paul Wolfowitz, President of the World Bank, and Randall Tobias, Director of the US Agency for International Development (USAID), have been in the US public spotlight for the last two weeks. The salacious details of their reasons for resigning (or being pressured to do so) have overshadowed the importance of these events for the global reproductive health community. Together, the World Bank and USAID control a very large portion of the funding globally available for reproductive health products, services and training. Under Wolfowitz and Tobias, both organizations have been involved in internal struggles over reproductive health policy and funding allocations.

In mid-April, World Bank staffers leaked revisions of a policy document that would have altered the Bank’s health strategy, “making women's access to reproductive health services, including abortions, more restrictive.” European governments and advocacy organizations from around the world lobbied intensively to remove the new language. The policy document has since been changed, and advocacy groups who have seen the new language report that it “now recognises the reproductive health rights of women.”

At USAID, Tobias oversaw a massive redirection of funds away from contraceptive research and development. With Tobias’ resignation, there is a new opportunity to reinstate full funding for these programs. MCC and MCIP will be collaborating on a letter-writing campaign, encouraging the more than 1,000 readers of the general public edition of this newsletter to make their voices heard as part of the upcoming Congressional appropriations process.

Read more:
The World Bank in turmoil, 5 May, The Lancet (Login required)
Tobias Resigns: What Next for Foreign Aid Reform?, 27 April, Center for Global Development

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WHO international clinical trial registry launched

Last week the World Health Organization (WHO) announced the launch of its International Clinical Trial Registry Platform (ICTRP). National-level trial registries have cooperated to launch the platform, including the US, Australian, New Zealand, Dutch, and various private pharmaceutical registries. Once registered, a trial is obliged to report its results, positive or not.

The mission of the registry is to ensure that a complete view of research is accessible to all those involved in health care decision making. This will improve research transparency and will ultimately strengthen the validity and value of the scientific evidence base. WHO adds that the registration of all interventional trials is a scientific, ethical and moral responsibility.

Learn more:
The newly launched ICTRP search portal
About the ICTRP

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Training clinicians to offer family planning services to men

Who will provide new contraceptives to men once they reach the market? Today in the US, many women receive reproductive health care, contraceptives, and family planning counseling through a network of federally funded clinics. Some of these clinics already offer reproductive health care services specifically for men, and there is a coordinated effort underway to expand the range of these services.

The 4,700 US family planning clinics receiving Title X funding from the federal government are eligible to participate in the Family Planning Male Training Center’s (FPMTC) annual meeting. The meeting offers clinical training and management tracks and draws nurses, outreach coordinators and Title X regional trainers who want to learn how to include men, the other half of the equation.

The FPMTC and affiliated doctors are working to create standard curricula for clinicians learning how to do a male reproductive health exam. In the US, there is currently no consensus on what training or qualifications are required to offer family planning services for men. As we move toward new birth control options for men, putting such guidelines in place will speed the introduction of these products.

Read more:
Office of Family Planning, Title X male involvement initiatives
Family Planning Male Training Center ’s statement of purpose

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In the news

The 20 April issue of Science (Vol. 316, No. 5823) contained a feature on germ cells, from their evolution to interactions with piRNAs to creating male germ cells from stem cells.

Coverage of Adjudin, male hormonal contraception and RISUG, based primarily on information provided by MCC’s website MaleContraceptives.org.
A birth control 'pill' for men?
Jamaica Gleaner, 15 April

Men’s and women’s views — and concerns — about the “male Pill” idea, such as this quote from Adam Wroblewski, age 29: "It's just another option… If both people are taking the pill, that's doubly safe."
Male pill idea may prove hard to swallow
Milwaukee Journal Sentinel, 26 April

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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.

May 6 - June 17	Frontiers in Reproduction lab and lecture course for research careers in reproductive biology; Woods Hole, MA, USA
May 20	Deadline for Florence-Utah Symposium abstract submission
May 29 - June 28	East-West Center’s 38th Summer Seminar on Population “Communicating with Policymakers about Population and Health” Workshop; Honolulu, HI, USA
June 2-5	89th Annual Meeting of The Endocrine Society, ENDO 07; Toronto, Canada
July 1-4	23rd Annual Meeting of the European Society of Human Reproduction and Embryology; Lyon, France
July 1-6	Gordon Research Conferences Cell-Cell Fusion; New London, NH, USA
July 15-20	Gordon Research Conferences Fertilization and Activation of Development; Plymouth, NH, USA
July 21-25	40th Annual Meeting of the Society for the Study of Reproduction; San Antonio, TX, USA
September 14-16	Florence-Utah International Symposium: Genetics of Male Infertility; Florence, Italy
September 26-29	53rd Annual Meeting of the Canadian Fertility and Andrology Society; Halifax, Nova Scotia, Canada
September 27-28	2nd Future of Male Contraception conference; Seattle, WA, USA
October 13-17	63rd Annual Meeting of the American Society for Reproductive Medicine; Washington, DC, USA
November 3-7	American Public Health Association 2007 Annual Meeting “Politics, Policy & Public Health”; Washington, DC, USA
2008
January 1	Deadline for European Society of Contraception abstract submission
April 30 - May 3	10th Congress of the European Society of Contraception; Prague, Czech Republic
May 3-7	10th European Congress of Endocrinology; Berlin, Germany

 

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Editors

Kirsten Thompson, Director of the Male Contraception Coalition (MCC)
Email: Kirsten@MaleContraceptives.org
Phone: +1 (510) 292-1186

Elaine Lissner, Director of the Male Contraception Information Project (MCIP)
Email: Lissner@NewMaleContraception.org
Phone: +1 (415) 863-1859 x107