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Review
“Male contraception remains under-used, as only male condoms are commonly used (apart from withdrawal and vasectomy). Consequently, new research protocols in the field of male contraception must be strongly encouraged.”
Non-deferential male contraception: review of the literature [French]
Huyghe E, Nohra J, Vezzosi D, Bennet A, Caron P, Mieusset R, Bujan L, Plante P.
Prog Urol. 2007 Apr;17(2):156-64.
PMID: 17489310
Motility targets
“We set out to identify proteins associating with CatSper that might help explain its unique role in spermatozoa. Using a transgenic approach, a CatSper1 complex was purified from mouse testis that contained HSP70-2, a testis-specific chaperone, and CatSper beta, a novel protein with 2 putative transmembrane spanning domains.”
Catsper beta: A novel transmembrane protein in the catsper channel complex.
Liu J, Xia J, Cho KH, Clapham DE, Ren D.
J Biol Chem. 2007 May 3; [Epub ahead of print]
PMID: 17478420
Endocrinological approaches
With a regimen of 100 mg/day T gel plus DMPA 300mg im/12weeks, the authors hypothesized “that men with incompletely suppressed spermatogenesis… would have higher intratesticular (iT) androgen concentrations than men who achieved severe oligospermia.” Levels of iT androgens did not differ between the groups. “Furthermore, there was no significant correlation between iT-T or iT-DHT and sperm concentration after 24 weeks of treatment.”
Intratesticular androgens and spermatogenesis during severe gonadotropin suppression induced by male hormonal contraceptive treatment.
Page ST, Kalhorn TF, Bremner WJ, Anawalt BD, Matsumoto AM, Amory JK.
J Androl. 2007 May 9; [Epub ahead of print]
PMID: 17494097
A proof of concept study exploring the effectiveness of combining heat and hormonal contraceptive regimens. The authors conclude that “heat causes a rapid and transient suppression of spermatogenesis. TU + Heat resulted in low sperm output that was maintained by continuous treatment with TU. Addition of an oral progestin accelerated spermatogenesis suppression by TU alone.”
Transient Scrotal Hyperthermia and Levonorgestrel Enhance Testosterone Induced Spermatogenesis Suppression in Men through Increased Germ Cell Apoptosis.
Wang C, Cui YG, Wang XH, Jia Y, Sinha Hikim A, Lue YH, Tong JS, Qian LX, Sha JH,
Zhou ZM, Hull L, Leung A, Swerdloff RS.
J Clin Endocrinol Metab. 2007 May 15; [Epub ahead of print]
PMID: 17504903
Endocrinological supporting research
A review of the pharmacokinetics, safety, side effects and benefits of TU.
More than eight years' hands-on experience with the novel long-acting parenteral testosterone undecanoate.
Saad F, Kamischke A, Yassin A, Zitzmann M, Schubert M, Jockenhel F, Behre HM,
Gooren L, Nieschlag E.
Asian J Androl. 2007 May;9(3):291-7.
PMID: 17486268
“We demonstrate that the human fetal testes express aromatase and ERβ simultaneously in Sertoli, Leydig and germ cells but are devoid of ERα. Quantification of positive cells indicates a window of protein expression, especially between 13 and 22–24 weeks… Our findings suggest that locally produced estrogens influence human testicular development through autocrine and paracrine mechanisms, most notably during the period of maximal testicular susceptibility to endocrine disruptors.”
Human fetal testis: source of estrogen and target of estrogen action.
Boukari K, Ciampi ML, Guiochon-Mantel A, Young J, Lombes M, Meduri G.
Hum Reprod. 2007 May 15; [Epub ahead of print]
PMID: 17504822
Cell adhesion targets
“…We summarize and provide some discussions on studies that focused on the role of cytokines in regulating junction restructuring events in epithelia from a molecular and biochemical perspective. Specifically, we use the adult rat or mouse testis as a model to highlight the significance of transcriptional and translational regulation.”
Regulation of cell junction dynamics by cytokines in the testis-A molecular and biochemical perspective.
Lui WY, Cheng CY.
Cytokine Growth Factor Rev. 2007 May 21; [Epub ahead of print]
PMID: 17521954
“In this report, we show that Rab4A associates with adherens junction signaling proteins in the testis… Administration of Adjudin to adult rats up-regulated the Rab4A level, which coincided with the loss of spermatocytes, round and elongate spermatids from the seminiferous epithelium.”
Rab4A GTPase - catenin interactions are involved in cell junction dynamics in the testis.
Mruk DD, Lau AS, Sarkar O, Xia W.
J Androl. 2007 May 9; [Epub ahead of print]
PMID: 17494101
Immunological approaches
“Using serum and seminal plasma of antisperm antibody-positive infertile adults and sera samples of prepubertal boys with testicular failure, we have extended the range of known immunogenic sperm proteins as well as identified some novel antigens (n = 6) of human sperm for further characterization.”
Application of proteomic methods for identification of sperm immunogenic antigens.
Domagala A, Pulido S, Kurpisz M, Herr JC.
Mol Hum Reprod. 2007 May 15; [Epub ahead of print]
PMID: 17507387
Human sperm protein encyclopedia and alloantigen index: Mining novel allo-antigens using sera from ASA-positive infertile patients and vasectomized men.
Shetty J, Bronson RA, Herr JC.
J Reprod Immunol. 2007 Jun 2; [Epub ahead of print]
PMID: 17548113
“Recombinant DE is able to both elicit a specific immune response and inhibit male and female fertility, supporting the use of this sperm epididymal protein for the development of an immunocontraceptive approach.”
Immunocontraceptive properties of recombinant sperm protein DE: implications for the development of novel contraceptives.
Ellerman DA, Busso D, Maldera JA, Cuasnicu PS.
Fertil Steril. 2007 May 3; [Epub ahead of print]
PMID: 17482178
Binding targets
“In order to exclusively study primary zona binding proteins, plasma membranes of sperm heads were isolated, highly purified and subsequently solubilized… Gel electrophoresis of ZP fragments with bound sperm proteins showed very reproducibly 24 sperm protein spots to be associated to the zona ghosts… [indicating] the involvement of multiple sperm proteins in ZP binding.”
Multiple proteins present in purified porcine sperm apical plasma membranes interact with the zona pellucida of the oocyte.
van Gestel RA, Brewis IA, Ashton PR, Brouwers JF, Gadella BM.
Mol Hum Reprod. 2007 May 3; [Epub ahead of print]
PMID: 17483085
Motility targets
“We show that the sNHE-null spermatozoa fail to develop the cAMP-dependent protein tyrosine phosphorylation that coincides with the functional maturation occurring upon incubation in capacitating conditions in vitro… [sNHE and sAC] appear to be components of a signaling complex at the sperm flagellar plasma membrane.”
A sperm-specific Na+/H+ exchanger (sNHE) is critical for expression and in vivo bicarbonate regulation of the soluble adenylyl cyclase (sAC).
Wang D, Hu J, Bobulescu IA, Quill TA, McLeroy P, Moe OW, Garbers DL.
Proc Natl Acad Sci U S A. 2007 May 17; [Epub ahead of print]
PMID: 17517652
Genomic/Proteomic supporting research
We “have identified several alternatively spliced transcripts encoding SP1 isoforms that display stage and cell-type-specific expression profiles in differentiating germ cells in the seminiferous epithelium of the testis. This review summarizes the expression patterns and functional significance of these SP1 transcription factor variants during spermatogenesis.”
SP1 transcription factors in male germ cell development and differentiation.
Thomas K, Wu J, Sung DY, Thompson W, Powell M, McCarrey J, Gibbs R, Walker W.
Mol Cell Endocrinol. 2007 May 30;270(1-2):1-7. Epub 2007 Mar 12.
PMID: 17462816
“High-level Tip60 gene expression is restricted to late pachytene and diplotene stages of sperm development. Likewise, the Mof gene is expressed at high levels in late pachytene and diplotene spermatocytes, but in contrast to Tip60, Mof is also expressed at high levels in round spermatids.”
The genes coding for the MYST family histone acetyltransferases, Tip60 and Mof, are expressed at high levels during sperm development.
Thomas T, Loveland KL, Voss AK.
Gene Expr Patterns. 2007 Mar 31; [Epub ahead of print]
PMID: 17517537
“In foetal, newborn and juvenile testes, Wsb2 mRNA and protein were readily detected in the seminiferous cords within both Sertoli and germ cells. Wsb2 mRNA was present in spermatogonia, spermatocytes and in Sertoli cells of the adult mouse testis… its expression in the first wave of spermatogenesis indicates a role in germ cells.”
Expression of Wsb2 in the developing and adult mouse testis.
Sarraj MA, McClive PJ, Szczepny A, Daggag H, Loveland KL, Sinclair AH.
Reproduction. 2007 Apr;133(4):753-761.
PMID: 17504919
A report of an “analysis of the proteome of human spermatozoa… [establishing] a 2-D gel electrophoresis (2-DE) reference map of human spermatozoal proteins in a pH range of 3.5-9.0”
Establishment of a high-resolution 2-D reference map of human spermatozoal proteins from 12 fertile sperm-bank donors.
Li LW, Fan LQ, Zhu WB, Nien HC, Sun BL, Luo KL, Liao TT, Tang L, Lu GX.
Asian J Androl. 2007 May;9(3):321-9.
PMID: 17486272
“In both the testis and epididymis, Cres mRNA was first detected on day 20, then it increased gradually from day 20 to day 70, and the high expression level maintained till day 420. In the testis, the Cres protein was exclusively localized to the elongating spermatids… The Cres protein was first detected on day 20 in the proximal caput epididymal epithelium… [and] the luminal fluid of the midcaput epididymis was also stained Cres-positive from day 35 on.”
Age-dependent expression of the cystatin-related epididymal spermatogenic (Cres) gene in mouse testis and epididymis.
Yuan Q, Guo QS, Cornwall GA, Xu C, Wang YF.
Asian J Androl. 2007 May;9(3):305-11.
PMID: 17486270
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Last month the Male Contraception Coalition launched a campaign to ensure adequate funding for US contraceptive research and development projects currently funded by the US Agency for International Development (USAID).
US House of Representatives subcommittee members received emails from around the country asking them to earmark set aside funds within the USAID budget for contraceptive research. This week, the Senate subcommittee will review the House’s recommendations. If you’d like to contribute your voice to this discussion, it’s not too late to tell the Senators what you think.
As you know, USAID and the NIH are the only public funding sources for contraceptive development and introduction in the US. Last year, an external review stated that USAID’s departure from this field would have devastating impacts; yet influential officials have advocated getting USAID out of the research business entirely. The 2008 budget will determine whether USAID can finish the contraceptive development it has started.
Restore funding to USAID’s contraceptive development initiatives by asking Congress to set aside funds.
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Several new findings of interest were presented as abstracts at the ENDO 2007 conference, held June 2-5 in Toronto, Canada. Excerpts of these abstracts are presented below. To read the full abstract or browse others, you’ll first need to register.
Potential Male Contraceptive Target: Germ Cell Specific Vasa Protein Localization in Monkey and Human Testis, from Kimberley Ma, Frank Berglund, Michelle Crespo, Yan-He Lue, Ronald Swerdloff, Amiya Sinha Hikim, Yi-Xun Liu, Yu-Gui Cui, Xing-Hai Wang, Jia-Hao Sha, Zou-Min Zhou, and Christina Wang
“Our study focuses on vasa (DDX4 or MvH), a specific meiotic and/or post-meiotic molecule essential for germ cell survival and development. Vasa is a member of the DEAD (Asp-Glu-Ala-Asp) box family of ATP-dependent RNA helicases and participates in RNA unwinding, translation initiation, and RNA turnover… In mice, vasa protein has been localized in spermatocytes and round spermatids and vasa knockout mice were infertile due to an arrest of spermatogenesis at zygotene spermatocytes. The objective of this study is to compare vasa protein expression and localization in rat, monkey and human testes… The vasa proteins were condensed in the chromatoid bodies of late spermatocytes and round spermatids. Our studies also confirm vasa as an evolutionarily conserved germ cell specific molecule, since vasa proteins were present in rat, monkey and human testes. The function of vasa will be determined in the monkey and human testes after interventions to regulate spermatogenesis. Further investigation of vasa in the human testes may lead to a potential target for male contraception.”
Protein Tyrosine Kinase Syk Is a Key Enzyme in Human Sperm Capacitation, from Luciana Bordin, Giulio Clari, Cristina Fiore, Donatella Pellati, Alessandro Borin, Donatella Fiorentin, and Decio Armanini
“We present evidence for a role of 72syk isoform, present in human spermatozoa in Tyr-phosphorylating sperm proteins, during capacitation… Anti-p72Syk immunostaining of samples showed the presence of this kinase in sperms… Our results demonstrate that Syk is mainly located in the [sperm] plasma membrane and at a lower extent also in cytosol and flagella, while head compartment reveals only trace of kinase. This represents the first evidence of a possible involvement of a src unrelated kinase in the capacitation-linked regulation of Tyr-P level of human sperms, underlying synergic participation of a second kinase, belonging to the syk family.”
Serum INSL3, a Leydig Cell Product, Does Not Correlate with Residual Intratesticular Androgens in Men with Suppressed Gonadotropins during Hormonal Contraceptive Treatment, from Stephanie T Page, Thomas F Kalhorn, William J Bremner, Bradley D Anawalt, Alvin M Matsumoto, and John K Amory
“20 healthy men, ages 18-55 years, enrolled in a 6-month study of transdermal testosterone (T) gel (100 mg daily) + depomedroxyprogesterone acetate (300 mg IM/12 wks) with or without the GnRH antagonist, acyline (300 g/kg SC/2 weeksx12 wks) were studied. During the 24th week of treatment, subjects underwent fine needle aspirations of the testes… After 24 weeks of male hormonal contraceptive treatment, LH and FSH levels were suppressed near the lower limit of detection (LH: 0.0370.01 IU/L, FSH: 0.170.5 IU/L). Serum INSL3 levels were suppressed significantly (baseline INSL3: 87686 pg/ml, week 24 of treatment INSL3: 98.513 pg/ml; p <0.001),… [but]Intratesticular T and intratesticular DHT did not correlate with serum INSL3… Serum INSL3, a circulating protein of Leydig cell origin, is not a good marker of intratesticular androgen biosynthesis in normal men after prolonged LH suppression induced by male hormonal contraceptive treatment. Additional studies to identify factors involved in persistent androgen biosynthesis, Leydig cell function, and spermatogenesis during gonadotropin suppression are warranted.”
New Models To Improve Safety of Testosterone Substitution by Pharmacogenetics and Obesity Status: Experience of 118 Treatment-Years with a Long-Acting Formulation of Testosterone Undecanoate, from Michael Zitzmann, Farid Saad, Eberhard Nieschlag
In hypogonadal men, treatment with intramuscular testosterone undecanoate “resulted in significant beneficial effects as serum levels of LDL-cholesterol, diastolic and systolic blood pressure as well as pulse rate decreased, erythropoeisis was stimulated and concentrations of HDL-cholesterol increased. Parameters remained stable after 4 injections. PSA levels did not exceed 2.9 ng/ml and no other adverse effects regarding the prostate were observed… Pathological safety parameters assessed opposite to the treatment trend (higher blood pressure, adverse lipid profiles) were due to insufficient androgen action (lower testosterone levels, longer AR CAG repeats) as well as higher BMI. Non-linear models to tailor androgen substitution involving testosterone dose, AR polymorphism and BMI are presented.”
The Effect of 5-Reductase Inhibition with Dutasteride and Finasteride on Semen Parameters and Serum Hormones in Healthy Men, from Richard V Clark, John K Amory, Christina Wang, Ronald S Swerdloff, Alvin M Matsumoto, Bradley D Anawalt, Susan E Walker, Lynda J Haberer, and William J Bremner
“We conducted a randomized, double-blinded, placebo-controlled trial in 99 healthy men randomly assigned to receive [the 5α-reductase inhibitors] dutasteride (0.5 mg), finasteride (5 mg) or placebo once daily for 1 year. Blood and semen samples were collected at baseline, at 26 and 52 weeks of treatment, and at 24 weeks post-treatment, and were assessed for T, DHT, and semen parameters. Dutasteride (D) and finasteride (F) significantly (P < 0.001) suppressed serum DHT compared with placebo (dutasteride, 94%; finasteride 73%), and transiently increased serum T. In both treatment groups, total sperm count compared to baseline was significantly (P <0.05) decreased at 26 weeks (D -28.6%, F -34.3%) but not at 52 weeks (D -24.9%, F -16.2%) nor at the 24 week follow-up (D -23.3%, F -6.2%)… There was a significant reduction of 612% in sperm motility during treatment with both dutasteride and finasteride and at follow-up. Neither treatment had any effect on sperm morphology.”
Gonadotropin-Regulated Testicular Helicase (GRTH/DDx25), a Master Regulator of Spermatogenesis, Prevents Testicular Germ Cell Apoptosis, from Ravi K Gutti, Chon-Hwa Tsai- Morris, and Maria L Dufau
“GRTH/Ddx25, a DEAD box RNA helicase,… functions as a component of mRNP particles and participates in gene specific mRNA export, protein translation, storage and regulation during sperm maturation. In GRTH null mice a severe apoptosis was observed in spermatocytes entering the metaphase of meiosis… Our studies demonstrated that GRTH, as a component of mRNP particles in addition to its several other functions, acts as a negative regulator of the Caspase pathway to control apoptosis in spermatocytes and promote the progress of spermatogenesis.”
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With manufacturing hurdles surmounted and training seminars for participating clinical staff completed, the new Phase III clinical trial of RISUG has officially begun. The first volunteers have now received RISUG; the clinical center in the central Indian city of Ludhiana is the first of four centers to start the trial. Investigators report not having any trouble finding volunteers, with 150 men already lined up at the New Delhi site and a couple dozen at a third site.
In previous studies, RISUG has been an effective contraceptive for at least 10 years, and in animal studies it has been reversible. This Phase III trial is designed to test the safety and efficacy of RISUG in a broad cross section of Indian men.
RISUG’s inventor and the Indian government are now beginning to explore international collaborations.
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Last week, the US Congress’ House of Representatives gave a much-needed $27.8 million increase to the nation's family planning program, Title X. This funding represents the greatest increase in 25 years, and is good news for the 4,500 clinics which use Title X funding to provide family planning services.
Democrats Compromise on Abstinence-Only Funding; Title X Increase
RH Reality Check, 8 June
Bayer Pharmaceuticals decides to drop out of a joint study of a hormonal male contraceptive delivered via injections plus implants; only Schering remains.
Bayer Breaks-Up With Male Contraceptive
Forbes, 8 June
A feature on the work of Dr. Yan Cheng’s lab to develop Adjudin.
Chemical Postmaster Helps Deliver Contraceptive to Testes
Population Briefs, 6 June
A long interview and profile of Dr. Joe Tash, the University of Kansas researcher who heads the lab which recently received a multi-million-dollar NIH grant to work on Gamendazole and other potential male contraceptives.
Sperm: The Final Frontier
The Pitch, 31 May
A feature on the work of UW researchers to develop a male hormonal contraceptive. A student view from Benjamin Lealofi: “The form of contraception that I would most prefer is the shot because I wouldn’t have to be responsible to take it every day.”
The future of contraception
UW Daily, 23 May
The city of Pune in India starts a campaign to popularize vasectomy and address myths.
With just 174 vasectomies, bureau plans PMT campaign
Indian Express, 3 May
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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.
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 2 |
Deadline for the World Congress on Men's Health abstract submission |
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 |
August 4-9 |
FASEB Summer Research Conference on the Biology of Cilia and Flagella; Saxtons River, VT, USA |
September 14-16 |
Florence-Utah International Symposium: Genetics of Male Infertility; Florence, Italy |
September 21-23 |
5th Biennial World Congress on Men's Health and Gender; Vienna, Austria |
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 |
September 30 |
Deadline for British Andrology Society abstract submission |
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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