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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 your colleagues can learn about your work in the next issue.
Immunological approaches
“To test the effects of the anti-CD46 autoantibody responses on spermatozoal function in vivo, we mated CD46/123-Ig-immune rats with naïve partners. Neither male nor female immune rats showed decreased fertility… [which] is likely a consequence of the considerable ‘redundancy’ in the rodent reproductive system.”
Immunization with autologous CD46 generates a strong autoantibody response in rats that targets spermatozoa.
Mizuno M, Harris CL, Morgan BP.
J Reprod Immunol. 2006 Sep 1; [Epub ahead of print]
PMID: 16950517
Report of distinct CD46 transcription patterns in various mouse genera. “Failure to express CD46 in Apodemus correlated with a consequent accelerated spontaneous AR time.”
Characterization and role of spermatozoal CD46 in outbred rodents.
Clift LE, Dvorakova K, Flanagan BF, Andrlikova P, Stopka P, Johnson PM.
J Reprod Immunol. 2006 Oct; 71(2):145-146. Epub 2006 Sep 14.
ScienceDirect
“Time-course fluorescence confocal microscopy… has been utilized to study the relationship between spontaneous AR, motility and cell death in human spermatozoa… 10% of spermatozoa remained viable and motile following AR.”
Surface detection of CD46 enables real-time visualization of the human spermatozoal acrosome reaction.
Cummerson JA, Harper CV, Johnson PM.
J Reprod Immunol. 2006 Oct; 71(2):160-161. Epub 2006 Sep 14.
ScienceDirect
Identification of 24 immunoreactive sperm proteins. A synthesized amino acid sequence from “a novel protein designated as a hypothetical protein FLJ32704… reacted with 90% of immunoinfertile sera…”
Molecular identities of human sperm proteins reactive with antibodies in sera of immunoinfertile women.
Bhande S, Naz RK.
Mol Reprod Dev. 2006 Sep 22; [Epub ahead of print]
PMID: 16998854
Isolation of a sperm alloantigen localized “within the radial spokes of the axonemal complex of the sperm flagellum,” although it is not testes specific. “[T]he protein plays a key role in axonemes across phyla.”
h-Meichroacidin, a morn repeat family member localized within the radial spokes of the sperm axoneme and epithelial cilia, is a human alloantigen.
Shetty J, Wolkowicz MJ, Klotz KL, Flickinger CJ, Herr JC.
J Reprod Immunol. 2006 Oct; 71(2):154-155. Epub 2006 Sep 14.
ScienceDirect
Heat-based approaches
Establishing baseline scrotal temperatures as a diagnostic guideline. Clothing increases scrotal temperature 30-37% regardless of body positioning. The difference between unclothed versus clothed scrotal temperatures in the “seated with legs crossed position” was less than expected, which indicates “the triggering of mechanisms whose function is to limit the increase of scrotal temperature.”
Effect of posture and clothing on scrotal temperature in fertile men.
Mieusset R, Bengoudifa B, Bujan L.
J Androl. 2006 Sep 6; [Epub ahead of print]
PMID: 16957137
Supporting research
CIB1, while not exclusively expressed in the testis, is shown as an essential protein in mouse spermatogenesis. Cib1 KO mice are morphologically normal and their “spermatogenic cells can complete both mitotic and meiotic divisions, [but] post-meiotic spermatids do not develop normally and sperm are not produced. We hypothesize that alterations in Sertoli cell function contribute to these defects…”
CIB1 is Essential for Mouse Spermatogenesis.
Yuan W, Leisner T, McFadden AW, Clark S, Hiller S, Maeda N, O'brien DA, Parise LV.
Mol Cell Biol. 2006 Sep 18; [Epub ahead of print]
PMID: 16982698
Report of bonnet monkey (Macaca radiata) epididymal sectioning and gene expression characterization. A homolog of the human whey acidic protein 10, mWFDC10A, was highly expressed in the monkey caput. The protein’s potential role as an immune defense mechanism is explored.
Differential expression and antibacterial activity of WFDC10A in the monkey epididymis.
Shayu D, Chennakesava CS, Rao AJ.
Mol Cell Endocrinol. 2006 Oct 19; 259(1-2):50-6. Epub 2006 Sep 20.
PMID: 16996203
Description of a class of apical secreted bodies produced along the length of the epididymis and enclosed in a bilayer membrane. “The fluidity of epididymosomes and sperm membranes evolved in opposite ways during epididymal sperm maturation,” suggesting a lipid exchange between the spermatozoa and vesicle membranes.
Lipid remodeling of murine epididymosomes and spermatozoa during epididymal maturation.
Rejraji H, Sion B, Prensier G, Carreras M, Motta C, Frenoux JM, Vericel E, Grizard G, Vernet P, Drevet JR.
Biol Reprod. 2006 Jun;74(6):1104-13. Epub 2006 Mar 1. Erratum in: Biol Reprod. 2006 Aug;75(2):306.
PMID: 16510839
At puberty, Sertoli cell (SC) specific androgen receptor KO mice showed disarranged SC nuclei, “functional defects in cytoskeletons and… disarranged basement membrane[s],… defects in intact junctional complex formation leading to impairment of [BTB] integrity,” and overall “impairment of [SC] germ cell nursery functions.”
Androgen Receptor in Sertoli Cell Is Essential For Germ Cell Nursery and Junctional Complex Formation in Mouse Testes.
Wang RS, Yeh S, Chen LM, Lin HY, Zhang C, Ni J, Wu CC, di Sant'agnese PA, de Mesy-Bentley KL, Tzeng CR, Chang C.
Endocrinology. 2006 Sep 14; [Epub ahead of print]
PMID: 16973730
Tests of 3 putative membrane progesterone receptor homologues from multiple species, and “found no evidence that human or fish mPRs regulate cAMP production or MAPK activation upon progesterone stimulation.” They conclude that their data do no support the responsibility of these mPRs for “transducing nongenomic progesterone actions.”
Human Homologs of the Putative G Protein-Coupled Membrane Progestin Receptors (mPRα, β, γ) Localize to the Endoplasmic Reticulum and are Not Activated by Progesterone.
Krietsch T, Fernandes MS, Kero J, Losel R, Heyens M, Lam EW, Huhtaniemi I, Brosens JJ, Gellersen B.
Mol Endocrinol. 2006 Sep 7; [Epub ahead of print]
PMID: 16959873
Reviews
Assessment of the best practices for contraceptive clinical trial design: allocation concealment and blinding, correctly defining “intention-to-treat”, the CONSORT versus Good Clinical Practice guidelines, the Pearl index versus life tables.
The Cochrane Fertility Regulation Group: synthesizing the best evidence about family planning.
Helmerhorst FM, Belfield T, Kulier R, Maitra N, O'brien P, Grimes DA.
Contraception. 2006 Oct;74(4):280-6. Epub 2006 Jun 19.
PMID: 16982225
“Testosterone, the male hormone, besides acting through its receptor expressed in the somatic cells of testis, seems to work by means of non-classical mechanisms. The recent identification of growth factors, transcriptional regulators, and media for in vitro growth of spermatogonial stem cells should now make it feasible to unravel the entire spermatogenic process.”
Signaling events during male germ cell differentiation: update, 2006.
Berruti G.
Front Biosci. 2006 Sep 1;11:2144-56.
PMID: 16720301
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From September 17th to the 22nd, researchers studying many facets of sperm biology came together in Madrid, Spain, for the 10th International Symposium on Spermatology. The abstracts summarized here represent only a small sample of the work presented – which ranged from the mechanisms of sperm motility, to sperm-zona binding, to sperm-Sertoli cell junctions. The complete set of abstracts can be downloaded as a PDF.
- Dr. Berruti and colleagues from the University of Milan presented their work on the role of GTPase Rap1 in mouse spermatogenesis, particularly its role in cell-cell adhesion. Male Rap1 KO mice (Rap1S17N) were “severely subfertile, whereas the transgenic females displayed normal fertility… [W]e found that interfering with Rap1 in haploid cells resulted in an anomalous release of immature spermatids within the lumen of seminiferous tubuli and in low sperm counts.” They hypothesize a role of Rap1 in the spermatid-Sertoli cell adherens junction, possibly via “a cAMP / Epac / Rap1 / VE-cadherin pathway in the formation and/or stabilization of apical Ectoplasmic Specialization.”
- Drs. Lyng and Shur of the Emory University School of Medicine summarized what is currently known about the receptor-ligand interactions involved in sperm-egg binding. While early studies identified β-1,4galactosyltransferase-1 (GalT) as a sperm receptor for egg ZP3 oligosaccharide ligands – and “GalT-null sperm show greatly reduced binding to ZP3 and are unable to undergo a zona-induced acrosome reaction" – “GalT-null sperm are still able to bind to the intact zona pellucida.” “The realization that successful sperm-egg binding results from the sequential action of molecularly distinct events” led to the search for GalT-independent receptors involved in the initial binding. One such has been identified as SED1, “also known as MFG-E8 and lactadherin,” which is acquired by sperm during epididymal transit.
- Dr. Perotti and colleagues from the University of Milan presented their work on identification and characterization of sperm surface compounds involved in dipteran gamete adhesion. Drosophila sperm membranes possess “four integral proteins with glycosidase activity”: two β-N-acetylhexosaminidases (HEXA and HEXB) an α-mannosidase and an α-L-fucosidase.” They have also identified the “genes encoding β -N-acetylhexosaminidases, Hexo1 (CG1318), Hexo2 (CG1787) and fdl (CG8824) and the gene coding for α-L-fucosidase (CG6128),… [with] fdl encod[ing] a homolog of the α-subunit of the mammalian β-N-acetylhexosaminidase Hex A.” “Immunofluorescence showed that the products of Hexo1, Hexo2, fdl and CG6128 mapped to distinct domains of the sperm plasma membrane… indicat[ing] a major role for these enzymes in fertilization.”
- Dr. Okabe and colleagues from Osaka University presented their work on null mice models in which sperm-egg binding does not occur normally. “Calmegin (Clgn), ADAM2, ADAM3 and Angiotensin-I Converting Enzyme (ACE) deficient mice exhibit male-specific infertility… In a previous study, we reported that in calmegin-deficient testes ADAM1/ADAM2 heterodimers disappeared and the sperm lacked ADAM2. We now show that ADAM3 was absent in Clgn deficient sperm. These data explain why the Clgn, Adam2 and Adam3 deficient sperm show similar phenotype.” Dr. Okabe also summarized work on Izumo, a sperm fusion factor. Izumo KO mice are healthy but infertile – their sperm binds to the ZP but does not fuse. In vitro tests of human sperm incubated with an Izumo antibody showed the same result.
- Dr. Vacquier and colleagues of the UCSD Scripps Institute of Oceanography presented their work on the ATP metabolism of sea urchin sperm flagella. They showed that creatine kinase (CK) and adenylate kinase (AK), both “located along the entire flagellum, and tightly bound to the axoneme” are essential to the “nonmitochondrial ATP synthesis in flagella,” with CK responsible for 60% and AK 40%. “AK has been assayed in both invertebrate and vertebrate sperm, but its contribution to total ATP synthesis remained unquantitated. Inhibitors of sperm-specific AKs are potential targets for contraceptive drugs.”
- Dr. Suarez and colleagues from Cornell University presented their work on the abnormal sperm of Ste5Jcs1 mutant mice. While mutant females show normal fertility, male Ste5Jcs1 mice are subfertile with reduced sperm motility. These sperm did not hyperactivate, and their flagellar midpieces were rigid, while the principal pieces beat asymmetrically. “Transmission electron micrographs of the midpiece showed normal axonemes and dense outer fibers, but apparently abnormal electron-lucent areas in the mitochondrial matrix…” This combined with the partial rescue of “the flagellar defect… by elevation of intracellular Ca2+” suggests that a mitochondrial defect may be responsible for the reduced motility.
A few of the research topics presented in the poster session:
- Drs. Alciaturi and Sapiro of the Montevideo School of Medicine presented their findings of a molecular study of Spag6, “a sperm central apparatus protein required for flagellar motility in mammals.” Male Spag6 KO mice are infertile with sperm morphological and motility defects. “[A]fter transfection with the constructs lacking the first [of 8 contiguous] armadillo repeats,” the protein no longer colocalized with microtubules. Even when just “its first amino acid was mutated, most transfected cells lost the tubulin pattern. These data suggest that the first armadillo repeats might directly or indirectly interact with tubulin and one AA could be essential to Spag6 function.” The authors note that their work may “offer new targets for contraception through the disruption of specific regions of the protein.”
- Dr. Vintém and colleagues presented their work on another potential motility target, a testis-specific isoform of protein phosphatase 1 (PP1γ2). “One particularly interesting mechanism for controlling PP1 activity involves inhibition by protein phosphatase inhibitor 2 (I2)… Here we describe the identification and preliminary characterization of a new isoform of I2 termed I2-L.” Recombinant I2-L and PP1γ2 “colocalize[d] in the sperm tail… We postulate that PP1γ2 and I2/I2-L may constitute attractive targets for the development of PP1 activity modulators for the treatment of impaired sperm motility and the development of male contraceptives.”
- Drs. Platt and van der Spoel of the Oxford Glycobiology Institute and Drs. Bone and Gottwald of Schering AG presented their tests of Miglustat (N-butyldeoxynojirimycin) as a contraceptive in various strains of mice and rabbits. Whereas miglustat had provided effective contraception in male C57BL/6 mice, its contraceptive effect was greatly reduced in other strains. Only at a dose three times greater than needed for C57BL/6 mice did “Miglustat disrupt the acrosomal staining pattern and the sperm head shape… in AKR/J, and Balb/c mice and in a number of C57BL/6-related strains.” The doses tested in rabbits did not have any affect on fertility, sperm morphology or motility, despite “the serum level of Miglustat in rabbits exceed[ing] the level of the contraceptive dose in C57BL/6 mice 17-times… The reasons for the strain/species variations with regard to the contraceptive effect of Miglustat have to be further elucidated.”
Next month: Highlights from the ASRM meeting
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Earlier this month, leaders of Wyeth’s Women’s Health Group made the decision to abandon their contraceptive discovery efforts. Six labs were involved in this research, which spanned both male and female putative contraceptive targets.
Mr. Gerald Burr of Wyeth’s public relations department characterized the group’s decision as a motivated by the bottom line, not by a lack of interesting potential targets. Indeed, Dr. Dan Johnston at Wyeth and his collaborators have recently submittedthe work presented at April’s American Society for Andrology meeting for publication, identifying over 1,000 genes expressed predominantly in the murine epididymis.
Speaking specifically of male contraceptive discovery, Mr. Burr said that “the development and commercialization landscape is really unclear.” He cited uncertainty about the size of the potential market and confusion about what service provision route would be used to deliver the product to men. Because the female contraceptive marketplace has become crowded and is now undercut by generic drugs, Wyeth’s business developers generally do not see contraceptive drugs as a profitable sector, despite the nearly untapped male contraceptive market.
While Wyeth will no longer have in their employ scientists researching new contraceptives for men, they remain interested in in-licensing promising products from other research entities. A member of Wyeth’s Business Development department is responsible for identifying potential collaborations of interest.
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RISUG is a polymer injected into the vas deferens which has proven reversible in animals and appears both safe and effective in men for over a decade per dose. On the road to potential commercial development, RISUG now faces a challenge which will determine its regulatory future. How the developers meet this challenge will determine whether RISUG may someday become available globally.
A short history: In the spring of 2006 – after a delay during which additional genotoxicity tests were conducted – RISUG researchers received government approval to re-initiate their Phase III clinical trial. They were ready to enroll hundreds of additional men at study centers throughout India but for one problem: they did not have RISUG material to conduct the study with. A public-private partnership with a pharmaceutical company had predicted product delivery by April 2005; yet a year after this target date, there was still a holdup.
Perhaps pouring extra effort into the existing manufacturing arrangement can produce top-quality material posthaste. The Indian government has sent a delegation to the manufacturing site to determine whether this is realistic, and policymakers are awaiting a report of the site visit team’s findings. But the speed and quality of the manufacturing process are not the only issues at stake – of equal import is how the manufacturing process is documented.
There are two possible guidelines the manufacturer can follow: the International Conference on Harmonization’s Good Manufacturing Practices (ICH GMP), or those of the World Health Organization (WHO GMP). On paper, ICH and WHO GMP standards are nearly the same, but in India, as in many countries, their enforcement differs. With a yearly budget less than what the US Pentagon spends in one day, the WHO cannot afford to maintain a centralized inspection staff and must rely on local officials for certification. This has the potential to introduce significant variation in enforcement rigor. Such variation means that companies must self-police their compliance, making ICH GMP certification the worldwide gold standard.
RISUG's manufacturing partner has experience with ICH GMP documentation – it makes other products to ICH GMP for markets in Britain and Australia. However, the current manufacturing contract specifies only WHO GMP standards. Taking advantage of this loophole to save time or money would risk rendering the Phase III trial results useless in the eyes of international regulatory agencies.
If this happens, the capital and time investment required by Phase III clinical trials would make repeating them with ICH GMP material extremely unlikely. Barriers to regulatory applications outside India would thus be nearly insurmountable. Furthermore, India is becoming more international every year. If India adopts the international ICH GMP standards during the next few years, the clinical trial would then be vulnerable to being stopped at any time during its five year span.
If RISUG is as effective, safe and convenient as trials have shown thus far, such barriers to availability would be a sad outcome. We hope regulators and developers will demand material made to ICH GMP.
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On September 19th, Organon and Schering announced that while they will continue to work on the development of male hormonal contraceptive products, they will do so separately. The results of the joint Schering/Organon Phase II trial of an etonogestrel implant + testosterone undecanoate injections (Implanon + Nebido) have not yet been published. This announcement suggested that while the method’s efficacy is acceptable, men in the trials were not pleased with the delivery method. A sociological study sponsored by Schering and published in 2005 indicated that men consider a pill to be the most desirable of the potential delivery methods.
• Read the Joint Schering / Organon press release.
• Read the 2005 study of men’s attitudes toward a new hormonal male contraceptives.
The cover of the September 7th issue of Nature featured the work of Chu et al. on sperm DNA-protein relationships. According to Chu, “Male fertility treatments go around the cause. No one knows the molecular basis of infertility… how the proteins work.” The article continues: “Her research concentrates on identifying these causes. The identification of the factors that function in fertility and reproduction could define new avenues for understanding human male infertility, finding appropriate treatments, and/or identifying male contraceptive methods.”
• Read the San Francisco State University press release.
The Australian Newsweek covered the work of Australian scientists on new contraceptive targets in men. The magazine profiled a researcher looking for new potential targets for male contraceptives who explains how investigators hunt for new drug targets. Also includes a discussion of Australian men’s and women’s attitudes toward male contraception.
• Read “The inconceivable truth about a male pill”.
Kenya’s largest newspaper, the Daily Nation, featured an opinion piece mentioning research on the IVD and suspensories.
• Read “Our men, too, should go for the pill”. (Requires registration.)
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The Association of Reproductive Health Professionals held their annual meeting in La Jolla at the beginning of September. The Male Contraception Information Project and the Male Contraception Coalition were there to raise awareness of the male contraceptives now in clinical trials: the Chinese and American designs of the Intra Vas Device; RISUG; and various male hormonal contraceptive formulations. Clinicians already field questions about the availability of new male contraceptives from their patients. Now they can direct clients to advocacy resources on the MaleContraceptives.org website, where folks can express their support of your work to policymakers and funders. The meeting was also a great opportunity for doctors and clinicians already providing no-scalpel vasectomies to learn about new methods in the pipeline.
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The Population Council’s Fellowship Coordinator, Aimee Lyons, posted this announcement on Androlog:
“Through a generous grant from the Fred H. Bixby Foundation, the Population Council has created a new Bixby Fellowship Program in part to expand opportunities for recently trained biomedical researchers. These fellowships will allow developing country nationals to work with experienced mentors in the Council's Center for Biomedical Research at Rockefeller University in New York City. Fellows will focus on projects in either the Council's Reproductive Health or HIV/AIDS Program. A description of the fellowship program and details about application procedures are available on the Council's website. For more information, please feel free to contact us at bixbyfellowship@popcouncil.org.”
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October 10-12 |
International Union for the Scientific Study of Population’s Seminar on the Ecology of the Male Life Course; near Marburg, Germany |
October 15 |
Deadline for International Workshop on the Epididymis abstract submission |
October 21-25 |
American Society for Reproductive Medicine 62nd Annual Meeting; New Orleans, LA, US |
October 22 |
ASRM CME course Male Contraception: Past, Present And Future; New Orleans, LA, US |
October 23-27 |
10th Summit Meeting on Male Hormonal Contraception; New York, NY, US |
October 26-30 |
2nd Asia-Pacific Forum on Andrology; Shanghai, China |
November 1 |
Deadline for American Society of Andrology meeting abstract submission |
November 5 |
Deadline for European Congress of Endocrinology abstract submission |
November 5-8 |
3rd International Conference on Experimental and Clinical Reproductive Immunology; Banff, British Columbia, Canada |
November 6-7 |
197 th Meeting of the Society for Endocrinology; London, UK |
November 11-14 |
American Medical Association House of Delegates Interim meeting; Las Vegas, NV, US |
November 12-16 |
28th Congress of the Societe Internationale d’Urologie; Cape Town, South Africa |
November 15 |
Deadline for British Society for Endocrinology meeting abstract submission |
November 15-18 |
52nd Annual Meeting of the Canadian Fertility and Andrology Society; Ottowa, Ontario, Canada |
November 16-18 |
British Andrology Society Annual Meeting on sperm function and maturation; Leeds, UK |
December 2-3 |
1st conference of the Ageing, Gender, Andrology & Sexual Sciences Society of India; Mumbai, India |
December 3-6 |
9th Congress of the European Society for Sexual Medicine; Vienna, Austria |
December 3-8 |
3o Encuentro iberoamericano de andrología; La Habana, Cuba |
December 4-7 |
4th International Workshop on the Epididymis; Chatel-Guyon, France |
December 8-10 |
4th European Congress of Andrology; Toulouse, France |
2007 |
January 12 |
Deadline for World Congress on Fertility and Sterility abstract submission |
March 5-8 |
Society for Endocrinology Annual BES Meeting; Birmingham, UK |
April 18-21 |
American Society of Andrology Testis Workshop; Tampa, FL, USA |
April 21-24 |
American Society of Andrology 32nd Annual Conference; Tampa, FL, USA |
April 25-27 |
20 Reunión Asociación Latinoamericana de Investigadores en Reprodución Humana; Buenos Aires, Argentina |
April 28 - May 2 |
9th European Congress of Endocrinology; Budapest, Hungary |
April 30 - May 5 |
IFFS 19th World Congress on Fertility and Sterility; Durban, South Africa |
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Editors
Kirsten Thompson, Director of the Male Contraceptive 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
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