MALE CONTRACEPTION UPDATE

Summaries of new peer-reviewed publications

A summary of new publications related to andrology and male contraceptive research categorized by contraceptive approach. Don’t see your journal article listed here? Do let us know so we can tell your colleagues about your work.

Endocrinological approaches
“Progestin coadministration increased both the rate and extent of suppression. Caucasian men suppressed sperm output faster initially but ultimately to a less complete extent than did non-Caucasians. Younger age and lower initial blood testosterone or sperm concentration were also associated with faster suppression, but the independent effect sizes for age and baseline testicular function were relatively small.”
Determinants of the Rate and Extent of Spermatogenic Suppression during Hormonal Male Contraception: An Integrated Analysis.
Liu PY, Swerdloff RS, Anawalt BD, Anderson RA, Bremner WJ, Elliesen J, Gu YQ, Kersemaekers WM, McLachlan RI, Meriggiola MC, Nieschlag E, Sitruk-Ware R, Vogelsong K, Wang XH, Wu FC, Zitzmann M, Handelsman DJ, Wang C.
J Clin Endocrinol Metab. 2008 Feb 26 [Epub ahead of print]
PMID: 18303073

Supporting endocrinological research
Following gonadotropin suppression using testosterone only or T+DMPA, the authors “demonstrated that gonadotrophins act as spermatogonial survival factors via the regulation of intrinsic apoptotic pathway, whereas [they have] no effect of cellular proliferation in [control] men.”
Gonadotrophins regulate germ cell survival, not proliferation, in normal adult men.
Ruwanpura SM, McLachlan RI, Matthiesson KL, Meachem SJ.
Hum Reprod. 2008 Feb;23(2):403-11.
PMID: 18199736

“We employed Cre-LoxP technology to generate male mice with prostate epithelial specific androgen receptor deficiency (denoted PEARKO). In addition to prostate, these males have reduced androgen action due to tissue-selective androgen receptor (AR) inactivation in seminal vesicle, epididymis and vas deferens, while the testis is unaffected… Despite normal testis sperm production, sperm numbers were reduced in caput but increased in cauda epididymis suggesting alterations in sperm epididymal transit kinetics associated with increased rate of spontaneous acrosome reaction and abnormal flagellar morphology in PEARKO cauda epididymal sperm.”
Severe subfertility in mice with AR inactivation in sex accessory organs, but not in testis.
Simanainen U, McNamara K, Davey RA, Zajac JD, Handelsman DJ.
Endocrinology. 2008 Mar 20 [Epub ahead of print]
PMID: 18356274

“An appraisal of the timing of Sertoli cell proliferation in other species, namely mouse and man, is presented. The current investigation may be useful in evaluating the potential influence of factors interfering with normal mitotic activity of Sertoli cells, including cell selection mechanisms, such as apoptosis, senescence, DNA repair and hormonal/paracrine growth modulation.”
Sertoli cell proliferation in the fetal and neonatal rat testis: A continuous phenomenon?
Angelopoulou R, Balla M, Lavranos G, Chalikias M, Kitsos C, Baka S, Kittas C.
Acta Histochem. 2008 Feb 25 [Epub ahead of print]
PMID: 18304617

Proteomic/genomic supporting research
A summary of the currently known markers of human sperm capacitation processes, sperm motility, sperm-egg fusion, and sperm acrosome reaction.
Molecular markers of human sperm functions.
Muratori M, Luconi M, Marchiani S, Forti G, Baldi E.
Int J Androl. 2008 Feb 20 [Epub ahead of print]
PMID: 18298567

“To study the function of Sohlh2 in germ cells, we generated mice harboring null alleles of Sohlh2. Male Sohlh2-deficient mice were infertile due to a block in spermatogenesis… [Undifferentiated] type-A spermatogonia isolated from Sohlh2-null mice proliferated normally, but linked the mutant phenotype to aberrant cell surface expression of the receptor-tyrosine kinase, cKit. Thus, Sohlh2 is required for progression of differentiating type-A spermatogonia into type-B spermatogonia.”
Sohlh2 Knockout Mice are Male Sterile Due to Degeneration of Differentiating Type-A Spermatogonia.
Hao J, Yamamoto M, Richardson TE, Chapman KM, Denard BS, Hammer RE, Zhao GQ, Hamra FK.
Stem Cells. 2008 Mar 13 [Epub ahead of print]
PMID: 18339773

“Here we report the identification of 858 proteins derived from mouse spermatozoa, 23 of which demonstrated testis only expression… [Our] list yielded three putative seven-transmembrane proteins, two of which have no known tissue distribution, an extragenomic progesterone receptor and three unique testis-specific kinases all of which may have some potential in the future regulation of male fertility.”
The mouse sperm proteome characterized via IPG strip prefractionation and LC-MS/MS identification.
Baker MA, Hetherington L, Reeves GM, Aitken RJ.
Proteomics. 2008 Mar 13 [Epub ahead of print]
PMID: 18340633

“A number of reports refining the whole sperm proteome e.g. tail proteins, membrane proteins, will be available in the next 12 months allowing a comprehensive first draft of the mature cell… Using this as a comparison to the proteome of other species, e.g. Drosophila, will answer fundamental questions such as: what is the basic machinery necessary to make a functionally mature male gamete?”
The human sperm proteome: the potential for new biomarkers of male fertility and a transformation in our understanding of the spermatozoon as a machine.
Barratt CL.
Hum Reprod. 2008 Feb 27 [Epub ahead of print]
PMID: 18305001

“We have shown that SOX8 protein is a product of adult Sertoli cells and its elimination results in an age-dependent deregulation of spermatogenesis, characterized by sloughing of spermatocytes and round spermatids, spermiation failure and a progressive disorganization of the spermatogenic cycle, which resulted in the inappropriate placement and juxtaposition of germ cell types within the epithelium. Those sperm that did enter the epididymides displayed abnormal motility.”
Sox8 is a critical regulator of adult Sertoli cell function and male fertility.
O'Bryan MK, Takada S, Kennedy CL, Scott G, Harada SI, Ray MK, Dai Q, Wilhelm D, de Kretser DM, Eddy EM, Koopman P, Mishina Y.
Dev Biol. 2008 Feb 13 [Epub ahead of print]
PMID: 18342849

Glycolipid metabolism targets
“To assess the role of these complex glycosphingolipids (GSLs) in spermatogenesis, we have now investigated with which of the testicular cell types these lipids are associated.” The GSLs first appeared around the time of pachytene spermatocytes. “Their synthesis is most likely driven by ceramide synthase-3. This enzyme is encoded by the Cers3/Lass3 gene, and out of 6 members of this gene family only Cers3 mRNA expression was limited to germ cells, where it was upregulated more than 700 fold during postnatal testicular maturation.”
Male germ cells require polyenoic sphingolipids with complex glycosylation for completion of meiosis: A link to ceramide synthase-3.
Rabionet M, van der Spoel AC, Chuang CC, von Tümpling-Radosta B, Litjens M, Bouwmeester D, Hellbusch CC, Körner C, Wiegandt H, Gorgas K, Platt FM, Gröne HJ, Sandhoff R.
J Biol Chem. 2008 Feb 27 [Epub ahead of print]
PMID: 18308723

Retinoic acid receptor approach
“Stra8… is essential for successful meiosis in both male and female gonads and normal spermatogenesis, [and] is directly related to the availability of retinoic acid (RA). This study examined the developmental expression pattern of Stra8 transcript in both male and female gonads, provided specific cellular localization of STRA8 protein in the postnatal and adult testis and investigated RA actions in adult germ cells in a vitamin A sufficient condition… STRA8 protein was localized to some type A and B spermatogonia, preleptotene spermatocytes and early leptotene spermatocytes. In the vitamin A sufficient adult testes, RA but not retinol acetate stimulated Stra8 mRNA expression. STRA8 protein expression in adult spermatogonia was induced by RA stimulation, suggesting its role in spermatogonial differentiation.”
Expression of Stimulated by Retinoic Acid Gene 8 (Stra8) in Spermatogenic Cells Induced by Retinoic Acid: An In Vivo Study in Vitamin A-Sufficient Postnatal Murine Testes.
Zhou Q, Nie R, Li Y, Friel P, Mitchell D, Hess RA, Small C, Griswold MD.
Biol Reprod. 2008 Mar 5 [Epub ahead of print]
PMID: 18322276

Gamete binding/fusion targets
“The extent of in vitro fertilization was reduced in a dose-dependent manner when unfertilized eggs were preincubated with recombinant ZP3R/sp56 [a mouse sperm protein localized in the acrosomal matrix] (74% drop at the maximum concentrations assayed).”
Recombinant mouse sperm ZP3-binding protein (ZP3R/sp56) forms a high order oligomer that binds eggs and inhibits mouse fertilization in vitro.
Buffone MG, Zhuang T, Ord TS, Hui L, Moss SB, Gerton GL.
J Biol Chem. 2008 Mar 3 [Epub ahead of print]
PMID: 18316377

Motility/capacitation targets
“PKA phosphorylation of p270 within 1 min of incubation under capacitation conditions suggests that this protein may have an important role in the initial signaling events that lead to the activation and subsequent hyperactivation of sperm motility.”
Bicarbonate-Induced phosphorylation of p270 protein in mouse sperm by cAMP-Dependent protein kinase.
Kaneto M, Krisfalusi M, Eddy EM, O'Brien DA, Miki K.
Mol Reprod Dev. 2007 Dec 19;75(6):1045-1053 [Epub ahead of print]
PMID: 18357561

Immunological approaches
“This is the first study to report the use of phage display technology to obtain antisperm single chain variable fragment (scFv) antibodies of defined antigen specificity. These antibodies will find clinical applications in the development of novel immunocontraceptives, and specific diagnostics for immunoinfertility.”
Isolation of human single chain variable fragment antibodies against specific sperm antigens for immunocontraceptive development.
Samuel AS, Naz RK.
Hum Reprod. 2008 Mar 28 [Epub ahead of print]
DOI: 10.1093/humrep/den088

Epididymal targets
“The presence of this adrenoceptor subtype in epididymal smooth muscle and epithelial cells indicates their contribution to smooth muscle contractile responses and a possible role in the absorptive and/or secretory activities of the epithelium lining the epididymal duct.”
Immunolocalization of alpha(1A)-adrenoceptors in rat and human epididymis.
Queiróz DB, Porto CS, Grossman G, Petrusz P, Avellar MC.
Cell Tissue Res. 2008 Mar 20 [Epub ahead of print]
PMID: 18351393

“[We] conclude that although both of eppin's domains are involved in the protein's antibacterial activity, only the Kunitz domain is required for selective protease inhibition.”
Functional domains of the human epididymal protease inhibitor, eppin.
McCrudden MT, Dafforn TR, Houston DF, Turkington PT, Timson DJ.
FEBS J. 2008 Mar 7 [Epub ahead of print]
PMID: 18331357

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SpermCheck device gets FDA approval

The FDA has approved the first home sperm count test that is calibrated to detect the very low sperm counts considered a sign of success for vasectomy and other male contraceptives, rather than the higher levels used in infertility diagnosis. The device, called SpermCheck Vasectomy, has a cutoff of 250,000 sperm/mL and will offer sufficient sensitivity to be used as a companion test for men using male contraceptives, as well as in the post-vasectomy period.

SpermCheck Vasectomy comes directly out of government agency-funded male contraception research support. Dr. John Herr, Director of the University of Virginia ’s Center for Research in Contraceptive and Reproductive Health, was originally looking at the SP-10 protein analyte as a contraceptive target. It didn't work out as a contraceptive target, but happily, researchers thought to put it to a different use. In a message to funders and colleagues, Dr. Herr credits the contraceptive research community: "Many of you have provided funding that directly supported the basic science underlying the device and others have worked on projects that provided the knowledge base regarding the SP-10 protein analyte measured in the test or engaged in clinical tests."

SpermCheck Vasectomy joins Fertell, a simple, recently-introduced test with a cutoff of 10 million motile sperm/mL, and Micra Home Sperm Analysis, a do-it-yourself home wet mount microscope with a cell-counting grid. Both of these over the counter products are available online for under $100.

With the addition of SpermCheck Vasectomy, expected to come to market as soon as this summer, the stage is now set for more confident, convenient use of future male contraceptives. Any future male contraceptive product with a slow onset of efficacy or long-acting formulation could benefit from the availability of this test. That includes hormonal regimens, CDB-4022, retinoic acid receptor antagonists, gamendazole, simple wet heat, and testicular ultrasound.

Read more
SpermCheck Vasectomy developers' University of Virginia press release
SpermCheck Vasectomy manufacturer ContraVac's website

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Male hormonal contraceptive meta-analysis makes news

A recent meta-analysis, authored by a who's-who of endocrine researchers, gained coverage in Fox News and the Washington Times. The analysis brings together data from 30 studies supporting the conclusion that adding a progestin to testosterone significantly increases the efficacy of hormonal male contraception, and that Asian versus Caucasian origin affects the speed of spermatogenic suppression.

Read more
Male Contraception Hormone Combination Gains Standing
MedPage Today, 26 March

Study: Progestin May Hold Key to Male Birth Control
Fox News, 25 March

Breakthrough claimed in male contraceptives
Washington Times, 26 March

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NIH funding opportunity deadline looms

Can you believe it's almost April? That means only a few weeks left to apply for the Male Contraceptive Development Program (RFA-HD-08-005). The first deadline — for a letter of intent — is April 16.

Dr. Diana Blithe of the National Institute of Child Health and Human Development urges researchers to apply to this program. “The aim of the program is to support both basic and applied research, with the ultimate goal of developing clinically useful products to regulate male fertility. This RFA solicits novel approaches to male contraception including, but not limited to, research on epididymal function, spermatogenesis, sperm function, and regulation of germ cell apoptosis… This funding opportunity will use the National Institutes of Health (NIH) specialized cooperative research award (U01) mechanism.”

We at IMCC and MCIP hope to see some great proposals competing for the NICHD's $2 million in 2008. Applicants may request up to $200,000 direct costs per year, for a period of up to 5 years. This RFA is perfect for anyone developing a male contraceptive who doesn't yet need millions. Consider applying even if your research isn't the hot thing – let the grantmakers choose their priorities among all options. We've been working for increased funding for years, so let's take advantage of it!

For further information, contact Diana Blithe.

Upcoming deadlines
Letters of Intent Receipt Date: April 16, 2008
Application Receipt Date: May 16, 2008

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Upcoming popular press articles

Any day now, the issue of Popular Science briefly covering male contraception research should be hitting newsstands. Popular Science is the world's largest science and technology magazine, with 6.5 million monthly readers and a bigger circulation than Vanity Fair, BusinessWeek, or the New Yorker. Hot on its heels will be a piece in Men's Health directing readers to the survey at MaleContraceptives.org. Look for ever-increasing public interest in, and demand for, your work.

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Male contraception in the press

A US News & World Report blogger and columnist wrote a thoughtful piece trying to digest the week’s male contraception news. If the “breakthrough” the press reported in hormonal male contraception is really more of an evolutionary step, what else is close to ready? Can men be selective about the type of contraceptive they choose to use without earning women’s scorn, or will some women only be satisfied if men suffer as they have? Check out the thought-provoking story and links, and add your opinion to the brief survey.

Should Men Care That Male Birth Control Options Are Languishing?
US News & World Report, 28 March

The hormonal male contraception meta-analysis gets fairly wide coverage, in Fox News, the Washington Times, and the Phillipines. The Washington Times article quotes MCIP's director Elaine Lissner for context: “Men are already using the only two contraceptives they have — condoms and vasectomy — in great numbers. At least in the United States, the idea that men aren’t willing to participate is clearly out of date... We used to talk about men ‘sharing the burden’ of contraception. But these days, many men talk about wanting ‘control.’ Men want to control their own destinies.”

Study: Progestin May Hold Key to Male Birth Control
Fox News, 25 March

Breakthrough claimed in male contraceptives
Washington Times, 26 March

Literatus: Oral options
Sun Star, 5 March

The Times of India and several other Indian press outlets published inaccurate information about RISUG development that appeared to be based on an interview with RISUG's developer but was not. Here’s what’s really happening: the Indian Council of Medical Research-run Phase III clinical trial in India is ongoing, and the developer and Indian government continue to explore potential collaborations for the development process both inside and outside India. We will keep you informed of any news.

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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.

April 12-15	33rd Annual Conference of the American Society of Andrology; Albuquerque, NM, USA
April 30 - May 3	10th Congress of the European Society of Contraception; Prague, Czech Republic
May 2-7	Joint meeting of the 15th European Testis Workshop and the Nordic Association for Andrology; Naantali, Finland
May 3-7	10th European Congress of Endocrinology; Berlin, Germany
May 5-7	Family Planning Male Training Center Annual meeting; San Diego, CA, USA
May 15	Deadline for American Society of Reproductive Medicine meeting abstract sumbission
May 16	Deadline for British Andrology Society abstract submission
May 22-23	Reproductive Health Supplies Coalition membership meeting; Brussels, Belgium
May 26-28	1st World Congress on Reproductive Biology; Kona, HI, USA
May 30	Deadline for 5th European Congress of Andrology abstract submission
June 9-15	International Men’s Health week
June 16	Deadline for Endocrine Society of Australia abstract submission
July 6-9	European Society for Human Reproduction and Embryology 24th Annual Meeting; Barcelona, Spain
July 6-11	Gordon Research Conferences – Ion Channels; Tilton, NH, USA
August 3-8	Gordon Research Conferences – Reproductive Tract Biology; Andover, NH, USA
August 25-28	Endocrine Society of Australia & Society for Reproductive Biology Annual Scientific Meeting; Melbourne, VIC, Australia
September 15	Deadline for Asia-Pacific Council on Contraception abstract submission
September 26	World Contraception Day
October 1-3	Androgens 2008, 5th Biennial Meeting on Androgen Receptor Function; Rotterdam, The Netherlands
October 15	Deadline for International Congress of Andrology abstract submission
October 22-25	30th Annual British Adrology Society Meeting; Gijon, Spain
October 25-28	2008 American Public Health Association Annual Meeting & Exposition; San Diego, CA, USA
November 8-12	American Society for Reproductive Medicine 64th Annual Meeting; San Francisco, CA, USA
November 26-28	5th European Congress of Andrology; Rome, Italy
December 4-6	Second Congress of the Asia-Pacific Council on Contraception (APCOC); Macao, China
2009
March 7-10	9th International Congress on Andrology; Barcelona, Spain

 

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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