A summary of new publications related to andrology and male contraceptive research categorized by contraceptive approach. Don’t see your recent journal article listed here? Let us know about it so your colleagues can learn about your work in the next issue.
Vas approaches
Chinese design of the intra vas device is a urethane plug with a nylon thread filter designed to halt sperm but allow vasal fluid to pass. When compared to no-scalpel vasectomy, the IVD group reported fewer complications, faster recovery and 93.4% contraceptive efficacy after 12 months.
“A phase II randomized controlled trial of a novel male contraception, an intra-vas device.”
Song L, Gu Y, Lu W, Liang X, Chen Z.
Int J Androl. 2006 Mar 27; [Epub ahead of print]
PMID: 16573708
Heat-based approaches
mRNA expression of testicular orphan receptors 3 and 4 was reduced after heat shock, but p53 mRNA expression increased dramatically. These “could be important regulators of germ cell apoptosis induced by heat treatment.”
“Expression of Orphan Receptors TR2, TR3, TR4, and p53 in Heat-Treated Testis of Cynomolgus Monkeys (Macaca fascicularis).”
Zhang XS, Yuan JX, Liu T, Lue YH, Jin X, Tao SX, Hu ZY, Hikim AP, Swerdloff RS, Wang C, Liu YX.
J Androl. 2006 May-Jun;27(3):405-13. Epub 2006 Feb 1.
PMID: 16452526
Sperm ion transport approaches
A new testis-specific calcium-dependent thiol protease localizes in the acrosome of cauda epididymis mouse spermatozoa.
“Calpain 11 is unique to mouse spermatogenic cells.”
Ben-Aharon I, Brown PR, Shalgi R, Eddy EM.
Mol Reprod Dev. 2006 Jun;73(6):767-73. Epub 2006 Mar 15.
PMID: 16541461
A method of measuring spermatozoa transmembrane ion currents. Confirms that Catsper1 KO mice sperm are not potentiated by intracellular alkalinization.
“Whole-cell patch-clamp measurements of spermatozoa reveal an alkaline-activated Ca2+ channel.”
Kirichok Y, Navarro B, Clapham DE.
Nature. 2006 Feb 9;439(7077):737-40.
PMID: 16467839
Cell adhesion targets
In rats, administration of Adjudin disrupts only Sertoli-germ cell anchoring junctions. Administration of the cytokine TGF-β3 disrupts both the junctions and the blood-testis barrier.
“Differential interactions between TGF-β3/TβR1, TAB1 and CD2AP selectively disrupt blood-testis barrier and Sertoli-germ cell adhesion.”
Xia W, Mruk DD, Lee WM, Cheng CY.
J Biol Chem. 2006 Apr 13; [Epub ahead of print]
PMID: 16617054
Sertoli-germ cell adhesion and the blood-testis barrier are disrupted by anti-laminin a3 and γ3 IgG blocking antibodies.
“Laminin alpha 3 forms a complex with beta 3 and gamma 3 chains that serves as the ligand for alpha 6beta 1-integrin at the apical ectoplasmic specialization in adult rat testes.”
Yan HH, Cheng CY.
J Biol Chem. 2006 Apr 11; [Epub ahead of print]
PMID: 16608848
Endocrine approaches
Meta analysis of various male hormonal contraceptive regimens shows “all individuals [taking an MHC] can expect to recover spermatogenesis to densities compatible with fertility.”
“Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis.”
Liu PY, Swerdloff RS, Christenson PD, Handelsman DJ, Wang C.
The Lancet. 2006 Apr 29;367(9520):1412-1420.
No PMID yet.
Men treated with cetrorelix, desogestrel and replacement testosterone showed reduced expression of 5α-reductase, inhibin α and acrosin binding protein.
“Direct effect of progestogen on gene expression in the testis during gonadotropin withdrawal and early suppression of spermatogenesis.”
Walton MJ, Bayne RA, Wallace I, Baird DT, Anderson RA.
J Clin Endocrinol Metab. 2006 Apr 18; [Epub ahead of print]
PMID: 16621906
Review of male hormonal contraceptive formulations, possible non-suppression mechanisms, and issues of market acceptability and regulatory agency approval.
“Male hormonal contraception: concept proven, product in sight?”
Matthiesson KL, McLachlan RI.
Hum Reprod Update. 2006 Apr 5; [Epub ahead of print]
PMID: 16597629
Comparison of 3 methods of counting sperm in severely oligo- or virtually azoospermic samples. Recommends “the use of large volume chambers and fluorescence microscopy.”
“Azoospermia: virtual reality or possible to quantify?”
Cooper TG, Hellenkemper B, Johckheere J, Callewaert N, Grootenhuis AJ, Kersemaekers WM, Leung A, Wang C.
J Androl. 2006 Apr 5; [Epub ahead of print]
PMID: 16598028
Review of male hormonal contraceptive formulations. Summary of the sociological research which establishes the “substantial unmet need” for reliable, reversible male contraception.
“Hormonal approaches to male contraception: Approaching reality.”
Wu FC.
Mol Cell Endocrinol. 2006 Mar 29; [Epub ahead of print]
PMID: 16580772
Estradiol biosynthesis catalyzers cytochrome P450 aromatase and 17β-hydroxysteroid dehydrogenase mRNA are present in the caput and cauda regions of the rat epididymis.
“Expression of functional aromatase in the epididymis: Role of androgens and LH in modulation of expression and activity.”
Shayu D, Rao AJ.
Mol Cell Endocrinol. 2006 Apr 25;249(1-2):40-50. Epub 2006 Mar 29.
PMID: 16569475
Progesterone receptors are found in the pituitary gland, hypothalamus, peritublar and interstitial testicular cells, epididymis, prostate and male mammary glands.
“Tissue expression of the nuclear progesterone receptor in male non-human primates and men.”
Luetjens CM, Didolkar A, Kliesch S, Paulus W, Jeibmann A, Boecker W, Nieschlag E, Simoni M.
J Endocrinol. 2006 Mar 24; [Epub ahead of print]
No PMID yet.
Rats treated with Acyline showed germ cell apoptosis “preceded by p38 MAPK activation and induction of iNOS,” which could be reduced by simultaneous administration of a selective iNOS inhibitor. Similar results in an in vitro human model.
“Involvement of p38 mitogen-activated protein kinase and inducible nitric oxide synthase in apoptotic signaling of murine and human male germ cells after hormone deprivation.”
Vera Y, Erkkila K, Wang C, Nunez C, Kyttanen S, Lue Y, Dunkel L, Swerdloff RS, Sinha Hikim AP.
Mol Endocrinol. 2006 Feb 9; [Epub ahead of print]
PMID: 16469770
Men in this study found the method acceptable overall, but thought monthly injections were an inconvenience.
“The acceptability of an injectable, once-a-month male contraceptive in China .”
Zhang L, Shah IH, Liu Y, Vogelsong KM, Zhang L.
Contraception. 2006 May;73(5):548-53. Epub 2006 Jan 20.
PMID: 16627044
Supporting research
Expression of genes in the initial segment of mouse epididymis is largely dependent on “testicular factors present in the duct fluid,” while caput genes are regulated by androgens. Also reports on epididymal genes up-regulated after gonadectomy, whose expression is mostly absent in controls.
“Differential Endocrine Regulation of Genes Enriched in Initial Segment and Distal Caput of the Mouse Epididymis as Revealed by Genome-Wide Expression Profiling.”
Sipila P, Pujianto DA, Shariatmadari R, Nikkila J, Lehtoranta M, Huhtaniemi IT, Poutanen M.
Biol Reprod. 2006 Apr 26; [Epub ahead of print]
PMID: 16641146
Murine equivalent of LDH-C4 is not testis-specific. Its mRNA is present in oocytes, but is not transcribed after fertilization – although the protein persists to the blastocyst stage.
“Testis-Specific Lactate Dehydrogenase (LDH-C4; Ldh3) in Murine Oocytes and Preimplantation Embryos.”
Coonrod S, Vitale A, Duan C, Bristol-Gould S, Herr J, Goldberg E.
J Androl. 2006 Apr 1; [Epub ahead of print]
PMID: 16582413
A protein expressed preferentially in the testis is also present in other tissues. TEX14 KO mice germ cells undergo “early meiotic death during the first cycle of spermatogenesis.”
“TEX14 is essential for intercellular bridges and fertility in male mice.”
Greenbaum MP, Yan W, Wu MH, Lin YN, Agno JE, Sharma M, Braun RE, Rajkovic A, Matzuk MM.
Proc Natl Acad Sci USA. 2006 Mar 28;103(13):4982-7. Epub 2006 Mar 20.
PMID: 16549803
“Infertility caused by polymorphisms or mutations in spermatogenesis-specific genes.”
Nishimune Y, Tanaka H.
J Androl. 2006 May-Jun;27(3):326-34. Epub 2006 Feb 10.
PMID: 16474012
“Growth factors and the epididymis.”
Tomsig JL, Turner TT.
J Androl. 2006 May-Jun;27(3):348-57. Epub 2006 Feb 10.
PMID: 16474016
Spindle-shaped cells in murine testicular interstitium are identified as stem Leydig cells.
“In search of rat stem Leydig cells: Identification, isolation, and lineage-specific development.”
Ge RS, Dong Q, Sottas CM, Papadopoulos V, Zirkin BR, Hardy MP.
Proc Natl Acad Sci U S A. 2006 Feb 8; [Epub ahead of print]
PMID: 16467141
A scaffolding protein present in the acrosomal region of mouse, bovine and human spermatozoa. Immunofluoresence tagging MUPP1 is shed after the acrosome reaction.
“The Multi PDZ Domain Protein MUPP1 as a Putative Scaffolding Protein for Organizing Signaling Complexes in the Acrosome of Mammalian Spermatozoa.”
Heydecke D, Meyer D, Ackermann F, Wilhelm B, Gudermann T, Boekhoff I.
J Androl. 2006 May-June;27(3):390-404. Epub 2006 Feb 1.
PMID: 16452527
Suggests that an immunofluorescence assay of tyrosine phosphorylation may be a clinically useful test of sperm ZP-binding capacity.
“Tyrosine phosphorylation on capacitated human sperm tail detected by immunofluorescence correlates strongly with sperm-zona pellucida (ZP) binding but not with the ZP-induced acrosome reaction.”
Liu DY, Clarke GN, Baker HW.
Hum Reprod. 2006 Apr;21(4):1002-8. Epub 2006 Jan 20.
PMID: 16428332
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This year’s ASA conference, chaired by Dr. Robert Oates, was held in Chicago April 8-11. Dr. Christina Wang began her tenure as ASA president, thanking outgoing president Dr. Sally Perrault Darney for all her work. One of the symposia, “Contraception – Beyond abstinence”, focused on the development of new male contraceptives. Dr. Michael O’Rand of the University of North Carolina, Dr. Erwin Goldberg of Northwestern University, and Dr. Daniel Johnston of Wyeth Research presented at this symposium.
Eppin: An effective target for male contraception
Dr. O’Rand summarized his findings on Eppin, a protein manufactured in the epididymis which binds to the surface of sperm. Dr. O’Rand described the interaction of Eppin, semenogelin and prostate specific antigen (PSA). After Eppin binds to a receptor on the surface of human spermatozoa, semenogelin binds to Eppin’s C-terminus. In this conformation, Eppin mediates the rate and extent of digestion of semenogelin by PSA, resulting in the slow dissolving of the coagulum and release of activation factors. When Eppin-semenogelin binding is blocked by Eppin antibodies, the result is immediate hydrolysis of semenogelin by PSA and the lack of a coagulum. Dr. O’Rand ’s group is now investigating exactly how Eppin binds to the sperm surface. He believes that Eppin is a promising target for male contraception, and said he is considering non-immunological contraceptive delivery models.
Testis specific gene products: Targets for contraceptive development
Dr. Goldberg reviewed the work of researchers elucidating sperm targets for contraception. These post-meiotic targets fall into the broad categories of (1)glycolytic enzymes, (2)ion channels and (3)signaling molecules. Dr. Goldberg suggested rational drug design and industry collaboration as the best approach to creating a contraceptive product aimed at these targets.
(1) Glycolysis is the main ATP pathway in sperm, so hampering glycolytic enzymes severely impairs motility. Dr. O’Brien’s group has shown that GapdS and PGK-2 null mice sperm are produced at normal rates, but have low ATP levels and virtually no progressive motility. Drs. Eddy and Goldberg have used oxamate to inhibit LDH-C4 action, but have not yet published results on an LDH-C4 null mouse.
(2) Calcium ion channels and sodium-hydrogen exchange channels create the potentiation needed for sperm motility. Dr. Clapham’s group has shown CatSper1 and 2 null mice sperm do not undergo hyperactivation. SNHE KO mice sperm also show impaired motility.
(3) Soluble adenyl cyclase (sAC) plays a role in sperm capacitation. sAC null mice sperm have little cAMP, AC or forward motility. They can, however, fertilize zona-free eggs since the sperm maintain a normal acrosome reaction.
Identification and development of novel targets for male contraception
Dr. Johnston summarized his work with Dr. Terry Turner on the epididymal genomics of both mouse and rat models. Wyeth is systematically identifying, characterizing and validating post-testicular targets. The ideal target would be located on the cell surface and receptive to a low molecular weight drug. Using Affymetrix microarrays, Dr. Johnston’s group has identified several dozen genes expressed predominantly in various segments of the mouse and rat epididymis. If these genes are not heavily expressed in other tissues, they may move to the next step of full characterization, and eventually the identification of possible contraceptive drug products using conformational matching. Dr. Johnston noted that he will gladly share the non-proprietary portions of this dataset with other researchers.
Next month
A summary of the proceedings of the 14th European Workshop on the Molecular and Cellular Endocrinology of the Testis
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NSF Request for applications – Biomolecular research
The National Science Foundation’s Division of Molecular and Cellular Biosciences offers rotating Biomolecular Systems Cluster grants for research emphasizing “the structure, function, dynamics, interactions, and interconversions of biological molecules. The context for such studies can range from investigations of individual macromolecules to the large-scale integration of metabolic and energetic processes. Research supported by this cluster includes development of cutting-edge technologies integrating theoretical, computational, and experimental approaches to the study of biological molecules and their functional complexes; mechanistic studies of the regulation and catalysis of enzymes and RNA, and higher-order characterization of the biochemical processes by which all organisms acquire, transform, and utilize energy from substrates.” The next application deadline is 12 July. For further information, contact Dr. Parag Chitnis.
NSF Request for applications – Cellular research
The National Science Foundation’s Division of Molecular and Cellular Biosciences offers rotating Cellular Systems Cluster grants for research focusing on the structure, function, and regulation of cells, and their interactions with one another. “Areas supported include studies of the structure, function, and assembly of cellular elements, such as the cytoskeleton, membranes, organelles, intracellular compartments, intranuclear structures, and extracellular matrix, including eukaryotic and prokaryotic cell walls and envelopes. In addition, support is provided for the study of intracellular and transmembrane signal transduction mechanisms and cell-cell signaling processes…” The next application deadline is 12 July. For further information, contact Dr. Eve Barak.
NICHD Program announcement – Reproductive genetics and epigenetics
On 12 April, the NICHD announced the reissue of the Reproductive Genetics and Epigenetics program funding (R21, R03, and R01, PA-06-346). The goal of the program is to support new studies of the genes, genetic and epigenetic mechanisms regulating fertility and reproductive health. Studies in this program will “identify and characterize the relevant genes, determine their function in normal human reproduction and reproductive development, identify functional partners or pathways and the nature of the interactions, and further our understanding of the consequences of mutations or dysregulation for human reproductive health. Studies of animal models are integral to this effort and are encouraged along with studies involving human subjects.” Grant recipients can receive up to $275,000 total over 2 years. Application opens on 2 May and closes 1 December. For further information contact Dr. Susan Taymanns.
NIH Program announcement - Clinical Trial planning
On 21 April, the National Institutes of Health announced a Clinical Trial Planning grant program (R34, PA-06-363). The goal of the program is to “provide support for the development of a Phase III clinical trial. This includes the establishment of the research team, the development of tools for data management and oversight of the research, the definition of recruitment strategies, and the finalization of the protocol and other essential elements of the study…” Grant recipients can receive up to $100,000 over 1 year. Application opens 2 May and lasts until 2009. For further information contact Dr. Eugene Hayunga.
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