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Motility targets
“We report characterization of a novel testis and sperm specific protein, FSCB [Fibrous Sheath CABYR Binding]… FSCB is a post meiotic protein first expressed at step 11 of mouse spermatogenesis in the elongating spermatids, and it subsequently incorporates into the flagellar principal piece of the sperm… Orthologous genes of FSCB are present in other mammals including rat and human and conserved motifs in FSCB include PXXP, proline-rich and extensin-like regions.”
FSCB: A novel PKA phosphorylated, calcium binding protein is a CABYR-binding partner involved in late steps of fibrous sheath biogenesis.
Li YF, He W, Jha KN, Klotz K, Kim YH, Mandal A, Pulido S, Digilio L, Flickinger CJ, Herr JC.
J Biol Chem. 2007 Sep 12; [Epub ahead of print]
PMID: 17855365
“Our results show that adenosine and catecholamine agonists act in a novel signaling pathway that does not involve G protein-coupled cell-surface receptors that link to conventional adenylyl cyclases. Instead, adenosine and analogs may be transported into sperm via equilibrative and concentrative nucleoside transporters to act on unknown intracellular targets.”
Adenosine and Catecholamine Agonists Speed the Flagellar Beat of Mammalian Sperm by a Non-Receptor-Mediated Mechanism.
Schuh SM, Hille B, Babcock DF.
Biol Reprod. 2007 Aug 29; [Epub ahead of print]
PMID: 17761644
RISUG
“Complete disintegration of the plasma membrane with subsequent rupture and dispersion of the acrosomal contents is observed on RISUG treatment. In the present study, micro-structural properties of human spermatozoa exposed to RISUG in vitro have been quantitatively analysed using atomic force microscopy.”
Quantitative analysis of surface micro-roughness alterations in human spermatozoa using atomic force microscopy.
Kumar S, Chaudhury K, Sen P, Guha SK.
J Microsc. 2007 Aug;227(Pt 2):118-23.
PMID: 17845707
Imino sugars
“Our findings suggest that in vivo alkylated imino sugars primarily interact with the non-lysosomal glucosylceramidase… ss-glucosidase 2 (GBA2),” disrupting the formation of the acrosome in a species and strain-dependent manner. “[It] appears that acrosome formation can be derailed by accumulation of glucosylceramide in an extralysosomal localization, and that the sensitivity of male germ cells to glucosylceramide is genetically determined.”
Accumulation of glucosylceramide in murine testis, caused by inhibition of β-glucosidase 2: Implications for spermatogenesis.
Walden CM, Sandhoff R, Chuang CC, Yildiz Y, Butters TD, Dwek RA, Platt FM, van der Spoel AC.
J Biol Chem. 2007 Sep 11; [Epub ahead of print]
PMID: 17848577
Endocrinological approaches
“Levonorgestrel butanoate (0.25, 1.0 and 2.5 mg kg(-1)) given as two injections on days 0 and 60 (groups II, III, IV) resulted in thickening and folding of the basement membrane and disruption of cell associations…” The middle LNG dose when administered with 40 mg of TB “was the most effective treatment in suppressing spermatogenesis. The site of action of this combination regimen is at the level of renewing Ad spermatogonia.”
Effects of levonorgestrel butanoate alone and in combination with testosterone buciclate on spermatogenesis in the bonnet monkey.
Sharma RS, Pal PC, Griffin PD, Waites GM, Rajalakshmi M.
Andrologia. 2007 Aug;39(4):117-23.
PMID: 17683459
Endocrinological supporting research
A report of the the pharmacokinetics of parenteral TU administration in hypogonadal men. “Following the treatment, there were no abnormally high/low plasma DHT levels… [Treatment] with testosterone undecanoate generates physiological levels of DHT. Prostate safety parameters did not undergo changes.”
Plasma levels of dihydrotestosterone remain in the normal range in men treated with long-acting parenteral testosterone undecanoate.
Yassin AA, Saad F.
Andrologia. 2007 Oct;39(5):181-4.
PMID: 17714216
Reports on the use of two computational models to predict endocrinopathy based on testis volume, sperm density, and motility measurements, instead of extensive serum assays. A neural network model (sensitivity 56%, specificity 97%) and logistic regression model (sensitivity 28%, specificity 99%) provided the most accurate predictions. “Reverse regression yielded P-values for the testis volume and sperm density of <0.0001… These models may be accessed via the Internet, allowing urologists to select patients for endocrinologic evaluation at http://www.urocomp.org.”
Computational models for detection of endocrinopathy in subfertile males.
Powell CR, Desai RA, Makhlouf AA, Sigman M, Jarow JP, Ross LS, Niederberger CS.
Int J Impot Res. 2007 Aug 23; [Epub ahead of print]
PMID: 17717523
“We showed in human sperm that androgen receptors [are] located at the head region… Human sperm express a functional AR that have the ability to modulate the PI3K/AKT pathway, on the basis of androgen concentration.”
Human sperm express a functional androgen receptor: effects on PI3K/AKT pathway.
Aquila S, Middea E, Catalano S, Marsico S, Lanzino M, Casaburi I, Barone I, Bruno R, Zupo S, Andò S.
Hum Reprod. 2007 Sept; 22(10):2594-2605. Epub ahead of print 2007Jul 26.
DOI: 10.1093/humrep/dem243
Supporting proteomic/genomic research
“[We] have shown, using a cohort-based approach, that there is no correlation between CAG repeat length expansion in the AR gene and semen quality.”
CAG repeat length variation in the Androgen Receptor gene is not associated with spermatogenic failure.
Westerveld H, Visser L, Tanck M, van der Veen F, Repping S.
Fert Ster. 2007 Sept 24; [Epub ahead of print]
PMID: 17889867
Vasectomy
“Immunohistochemical expression of occludin and connexin 43 were decreased in the testis after vasal and epididymal ligation… [Tight] and gap junctions were more disrupted after vasal obstruction than epididymal obstruction. This finding is of interest. Although the physiological role of gap junctions in the epididymis is not clearly identified, the difference between the two models may be because of strong structures within the epididymal TJs. The blood–epididymal barrier may absorb the negative effects of such inflammatory and obstructive process per se.”
Immunohistochemical expression of connexin 43 and occludin in the rat testis after epididymal and vasal ligation.
Altay B, Turna B, Öktem G, Aktuğ H, Semerci B, Bilir A.
Fert Ster. 2007 Sept 6; [Epub ahead of print]
PMID: 17825302
Immunological supporting research
“To our knowledge, this is the most extensive study to date providing information on concentrations of immunologic factors including cytokines, chemokines, growth factors, Igs and PMN in the semen of healthy fertile men. In addition to confirming and extending earlier studies that have documented a variety of cytokines and other immunologic factors in normal human semen, we demonstrate for the first time the presence of the chemokine SDF-1{alpha}, and the cytokines IL-5, IL-7, IL-13 and IL-17 in normal human semen.”
Concentrations and significance of cytokines and other immunologic factors in semen of healthy fertile men.
Politch JA, Tucker L, Bowman FP, Anderson DJ.
Hum Reprod. 2007 Sept 12; [Epub ahead of print]
DOI: 10.1093/humrep/dem281
Male germ line
A comment on Yoshida et al. (2007), descibing the use of live imaging to reveal that the location of germline stem cells in mouse seminiferous tubules may be determined by the location of interstitial blood vessels.
Home for the precious few.
DiNardo S, Braun RE.
Science. 2007 Sep 21;317(5845):1696-7.
PMID: 17885122
“[We] revealed a biased localization of A(undiff) [fluorescent protein-labeled undifferentiated spermatogonia] to the vascular network and accompanying Leydig and other interstitial cells, in intact testes. Differentiating spermatogonia left these niche regions and dispersed throughout the basal compartment of the seminiferous epithelium. Moreover, rearrangement of A(undiff) accompanied the vasculature alteration.”
A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis.
Yoshida S, Sukeno M, Nabeshima Y.
Science. 2007 Sep 21;317(5845):1722-6. Epub 2007 Sep 6.
PMID: 17823316
Andrology general interest
Andrology Australia is a unique government-funded program providing male reproductive health information and education for both members of the general public and GPs. “The main access to Andrology Australia is through its website www.andrologyaustralia.org… Downloadable fact sheets are available on line for patients and GP summary sheets are available for medical practitioners, who also have available accredited on line medical education modules.”
Andrology Australia – a description of a unique service providing information on male reproductive health problems to the Australian public and medical practitioners.
Lowy M.
J Men’s Health Gend. 2007 Sept; 4(3):357. Epub 2007 Aug 22.
DOI: j.jmhg.2007.07.002
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About 120 laboratory and clinical investigators came together in Seattle, Washington, last week to share their most recent findings on a range of avenues of male fertility control. Presentations ranged from clinical findings of new male hormonal contraception formulations to pre-clinical sperm-specific targets to new drug development. The meeting was featured above the fold on the front page of the Seattle Times, and many other news outlets around the country followed suit. Thanks are due to the meeting’s sponsors (NICHD, CONRAD, the WHO and the University of Washington, with logistics by Health Decisions) for a smooth-running and inspiring conference that sent participants away with new ideas and renewed energy.
For a full look at the topics covered, you will be able to read all presented abstracts on the conference site: FutureOfMaleContraception.com. What follows here are a few of the most intriguing new findings, impressive results, and unanswered questions.
- Dr. Wendy Kersemaekers of Organon presented the results of the Phase II trial of ENG rods (Implanon) plus TU depot injections (Nebido) as a male hormonal contraceptive (MHC). The most effective regimen was a high release ENG rod plus 750 mg TU every 10 weeks, with 94% of men reaching <1million sperm/mL and 97% maintaining this spermatogenic suppression.
- Dr. Eberhard Nieschlag of the University of Muenster presented findings on the relative gonadotropin suppressing efficacy of various oral and transdermal progestins in men. Cyproterone acetate (CPA, 10 or 20 mg/day) and norethisterone acetate (NETA, 10 mg/day) were markedly more effective than the other tested progestins.
- Dr. David Clapham of Harvard University presented a comprehensive picture of what is currently known about CatSper. All 4 of the CatSper proteins are required for sperm hyperactivation. The greatest challenge facing CatSper as a potential contraceptive target is the difficulty of expressing CatSpers in other cells. Without a non-sperm expression system, the process of drug assay will be ponderously slow.
- Dr. Barbara Attardi of Bioqual presented a newly developed, orally active androgen, dimethandrolone undecanoate (DMAU). Because DMAU also exhibits progestational activity, it could be a single agent MHC. Dr. Attardi is currently carrying out dose-finding studies in rabbits; a full toxicology profile is still required.
- Dr. Yan Cheng of the Population Council proposed the window of Sertoli cell disassembly – when a phase VII or VIII spermatocyte passes through the blood-testis barrier – as an opportunity for testicular drug delivery, generating much discussion. His lab is working to elucidate the exact mechanisms of this tight junction and apical ectoplasmic specialization restructuring.
- Dr. Debra Wolgemuth of Columbia University presented findings on the use of a retinoic acid receptor (RAR) antagonist as a male contraceptive. After one week of treatment with low doses of an RAR pan-antagonist, mice showed spermatogenic arrest, with step VIII and IX spermatocytes remaining entrenched in Sertoli cells. Full fertility returned within 4 months. Reversibility after long-term treatment remains unknown.
- Dr. Sheri Hild presented l-CDB-4022, which impaired mature sperm cells in monkeys with full recovery by week 16.
- Dr. John Amory of the University of Washington presented some unexpected findings on oral administration of testosterone enanthate (TE). Co-administration with dutasteride increased the efficacy of oral TE; food had no affect on uptake. This regimen resulted in a significant suppression of FSH, but poor LH suppression, perhaps due to high serum estradiol levels. Drs. Bremner and Amory are collaborating with Dr. Richard Clark of Glaxo Smith Kline on nano-milled oral testosterone preparations for a MHC.
- Dr. Stephanie Page spoke on a regimen using DMPA + testosterone gel, two products already on the market.
- Dr. Peter Liu gave a meta-analysis of fertility return after hormonal contraception: among other findings, faster recovery correlated with shorter use (but maximum treatment was 1.5 years).
- Dr. Chris Boelter of Shepherd Medical Company presented preliminary 3-month and 6-month azoospermia numbers for the Intra Vas Device, currently similar to numbers for vasectomy without fascial interposition.
- Dr. Albert Radlmaier of Bayer Schering Pharma AG presented two studies of the acceptability of an MHC, firstly for men and secondly for health care providers. The focus group studies showed that men were generally positive about the Implanon + Nebido MHC, with acceptability increasing after they had seen and touched the Implanon rod and applicator. Physicians, on the other hand, were generally negative about the method, and desired further information about safety and side effects.
- Dr. Gunda Georg of the University of Minnesota described the services of her new high throughput screening facility, which she offered to all present. She also outlined the progress her HTS lab has made toward novel male contraceptive drug identification.
Top photo: Dr. Diana Blithe, Jean Fourcroy, and Dr. Trent MacKay. Middle photo: Dr. Eugene Xu, Kirsten Thompson, Elaine Lissner, Dr. Debra Wolgemuth. Bottom photo: Drs. Doug Colvard, Michael Harper, Patricia Cuasnicu, and Gustavo Doncel.
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Fertility and Sterility has issued a supplemental issue (Vol. 88, S1) containing all the abstracts and posters to be presented at the 63rd annual American Society for Reproductive Medicine meeting coming up in Washington, DC, from October 13th to 17th.
Extracellular guidance cues in regulating sperm motility.
J.H. Lee, Y. Liu, L. Mei, W.C. Xiong.
Neurology, Institute of Molecular Medicine and Genetics, Augusta, GA.
“Molecular mechanisms underlying mammalian sperm motility and guidance are largely unknown. Previously, we characterized netrin-1 as a neuronal axon guidance cues.” Here data are presented showing the expression of netrin-1 mRNA and protein in mouse testes. “Our results suggest a novel function of netrin-1 and reveal a new mechanism of regulation of sperm motility and guidance.”
Phospholipase D mediates motility in sperm capacitation.
S. Bar-Sheshet Itach, S. Rubinstein, H. Breitbart.
Bar-Ilan University, Ramat-Gan, Israel.
“Sperm incubated in capacitation medium revealed a time dependent increase in actin polymerization followed by the development of hyperactivated motility. Actin polymerization and sperm motility were blocked by the phospholipase D (PLD) inhibitor butan-1-ol but not by butan-2-ol, indicating the specificity of the inhibitor… Furthermore, activation of protein kinase C, which activates PLD, induced actin polymerization that was followed by an increase in hyperactivated motility. Addition of cytochalasin D (a known inhibitor of actin polymerization), blocked both actin polymerization and hyperactived motility during capacitation.”
Possible involvement of interleukin-1 family in the regulation of male mouse fertility.
M. Huleihel, M. Ganaiem, M. Abu Elhija, T. Eldar-Geva, N. Weisz, E. Lunenfeld.
Ben-Gurion University of the Negev, Beer-Sheva, Israel; Soroka University Medical Center, Beer-Sheva, Israel; Shaare Zedek Medical Center, Jerusalem, Israel.
“IL-1α KO mice showed a significant reduction (40%; P<0.05) in their capacity to fertilize WT females… Also, the number of fertilized oocytes in vitro (IVF) and the number of cells in the fertilized oocytes were significantly lower using spermatozoa from IL-1α KO as compared to WT. AR could not be induced in spermatozoa from IL-1α KO mice by ionophore, as compared to spermatozoa from WT mice… IL-1α may play an essential role in sperm production in the testis and/or sperm motility in the epididymis. Our study suggests an essential role for IL-1α mouse in sperm morphology, function and male fertility.”
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NICHD issued a program announcement for the Americas Fellowship in Reproductive Sciences, providing “a unique opportunity to qualified Latin American reproductive scientists, at junior or mid-career level[s], to receive up to three years of research training in the United States or Canada.” NICHD requests a Letter of Intent by November 8th.
The Rapid Access to Interventional Development (RAID) pilot of the NIH Roadmap program may be good source of support for male contraceptive developers. The intent of the RAID program is to reduce common barriers between laboratory discovery and clinical application via services offered. It is not a grant mechanism, but a set of services available to qualified applicants. Services include the synthesis of small molecules and peptides (GMP or non), initial toxicology workups, product development planning, and help with regulatory aspects. Intellectual property rights remain with the originating institution. Partnership with or licensing to a for-profit company is encouraged. Investigators are strongly encouraged to apply to this program as soon as possible; as it becomes better known, the percentage of applicants receiving funding will go down.
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Alerted to it by the Male Contraception Information Project's press release, Seattle's largest daily paper featured the "Future of Male Contraception" conference in a well-researched and largely accurate article. Includes interviews with Dr. Bill Bremner of UW and Elaine Lissner of MCIP. Focuses on attitudes and hormonal approaches, but "not all researchers are putting their eggs in the hormone basket." Ends with brief mentions of the IVD (and reversibility questions), the RISUG clinical trial, and heat treatments.
Men on "the pill"? Doctors say it's no dream
Seattle Times, 27 September
Seattle's other major daily paper also featured the conference, with a focus on the University of Washington's role. "For the past two decades, researchers have tried to provide men with more choices in contraception. Women have the pill, intrauterine devices, injections, birth control patches, female condoms and the sponge. Men have basically two choices: condom or vasectomy. Although both methods work pretty well, they each have drawbacks. Many researchers say men should have more options and more of a shared responsibility..."
Breakthrough in male birth control remains elusive -- But it's only a matter of time, researchers say
Seattle Post-Intelligencer, 27 September
The University of Washington's student paper gets in on the act with a front page story.
Male contraceptives coming down the pipeline
The UW Daily, September 28
LiveScience covers the highlights from the first day of the conference, working from MCIP's press release; the story then gets picked up by msnbc.com (with a few inaccuracies introduced along the way). Covers the IVD, James Dalton's SARM work, and BIOQUAL's CDB-4022 study.
Birth control pills for guys could be reality soon
MSNBC, 28 September
More coverage of the first day of the conference; highlights CDB-4022, dimethandrolone undecanoate, and SpermCheck. "For decades, pundits have predicted new contraceptives for men within the next 5 to 10 years. Are we really getting any closer? Judging from work presented today at the second 'Future of Male Contraception' conference, the answer may finally be yes."
Contraception: progress brings hope for new methods for men
PHYSORG.com, 28 September
A nicely-done story based on news from the second day of the conference. Adds in statistics about unwanted pregnancies and the need in both the U.S. and abroad. Covers Dr. Debra Wolgemuth's work, the T-gel + DMPA study from the University of Washington, and the IVD Phase I trial results. One error: it implies fertility return after IVD reversal is already known.
Conference Reveals Promising Options for Male Contraception
Associated Content, 29 September
Health Canada gives approval for the first preliminary Canadian trials of the Intra Vas Device, after the interim results of the U.S. Phase I clinical trial prove acceptable. This article also shows confusion on the reversibility issue.
Studies begin into reversible male contraceptive
CTV.ca, 28 September
An engaging clip on Seattle's major news-talk radio station gets the man on the street's reaction to the idea of using a new method and packs in commentary from both Bill Bremner and MCIP. This 2-minute feature made the 6:00 news. Available as a podcast or for listening online!
Male Contraception
710 KIRO, 28 September
Coverage from earlier in the month:
As in the FMC presentation, Bayer's decision to quit male contraceptive research is described as a part of a strategic focus on high-profit areas: "Bayer's research efforts are focused on four areas that it views as having especially high growth potential: cancer treatment, cardiology, women's health care and diagnostic imaging (such as X-rays and MRIs). In an effort to make its research and development more fruitful, the company has initiated a process that determines whether projects are likely to be commercial as well as scientific successes. As a result, it has abandoned efforts to develop certain kinds of antibiotics and a male contraceptive."
Prescriptions for Growth
Barron's, 3 September
A lengthy look at the Scottish hormonal contraceptive study and the hurdles commercialization faces. "For Steven Driver, the decision to try out a new male pill was a simple one. His long-term girlfriend had struggled with the side-effects of her own contraceptives for 11 years and he felt it only right that he take his turn..."
A hard pill to swallow
The Scotsman, 16 September
Attitudes towards male contraception among a more conservative than average group of young people, undergraduates at Utah State University (many of them married). Acknowledges the side effects women have from female contraceptives; many of the women's husbands are not eager to sign up for something similar, or think they would forget to take a daily method.
The future of male birth control
The Utah Statesman, 19 September
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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.
October 13-17 |
63rd Annual Meeting of the American Society for Reproductive Medicine; Washington, DC, USA |
November 1 |
Deadline for American Society of Andrology abstract submission |
November 3-7 |
American Public Health Association 2007 Annual Meeting “Politics, Policy & Public Health”; Washington, DC, USA |
November 15-16 |
British Andrology Society Annual Meeting; Ware, Hertfordshire, UK |
November 16-18 |
2nd Japan - ASEAN Men's Health & Aging Conference; Ishikawa, Japan |
2008 |
January 1 |
Deadline for European Society of Contraception abstract submission |
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 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 (443) 858-1183
Elaine Lissner, Director of the Male Contraception Information Project (MCIP)
Email: Lissner@NewMaleContraception.org
Phone: +1 (415) 863-1859 x107
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