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.
Epididymal targets
Connective tissue septa between the epididymal lobules “limit the effect of interstitial paracrine molecules and provide a physiological rationale for the phenomenon of segmented epididymal gene expression.” Focuses on the presence, activity and potential target genes of growth factors “EGF, basic FGF (FGF2) and VEGFA in segments 1 and 2 of the rat epididymis.”
“Growth Factor-Stimulated Extracellular Signal-Regulated Protein Kinase (ERK) Phosphorylation in the Rat Epididymis is Limited by Segmental Boundaries.”
Tomsig JL, Usanovic S, Turner TT.
Biol Reprod. 2006 Jul 19; [Epub ahead of print]
PMID: 16855209
Endocrine approaches
Contains a summary of the published works on selective androgen receptor modulators (SARMs) which have characteristics suitable for use as male contraceptives.
“Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands.”
Gao W, Kim J, Dalton JT.
Pharm Res. 2006 Jul 14; [Epub ahead of print]
PMID: 16841196
Dose-finding study for im TU and NET-E. “We conclude that despite some accumulation of T, TU 1000 mg + NET-E 200 mg administered every 8 weeks may be preferable for the future contraceptive efficacy study because of more complete suppression of gonadotropins and spermatogenesis.”
“Pharmacokinetics of Testosterone Undecanoate Injected Alone or in Combination with Norethisterone Enanthate in Healthy Men.”
Qoubaitary A, Meriggiola C, Ng CM, Lumbreras L, Cerpolini S, Pelusi G, Christensen PD, Hull L, Swerdloff RS, Wang C.
J Androl. 2006 Jul 12; [Epub ahead of print]
PMID: 16837736
“Direct evidence for progestogenic effects on all three major compartments of the testis, i.e. steroidogenesis (5α-reductase), Sertoli cell function (inhibin α), and spermatogenesis (ACRBP), independent of gonadotropin inhibition.” The authors underscore the role of “5 α-reduction and disruption of spermiation as important components of the testicular response to gonadotropin withdrawal, of direct relevance to [an] understanding of testicular function and development of novel methods of male contraception.”
“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 Jul;91(7):2526-33. Epub 2006 Apr 18.
PMID: 16621906
A summary of male hormonal contraceptive trials outlining the involvement of the World Health Organization, CONRAD, the Population Council, research universities and pharmaceutical companies. Concludes that testosterone/progestin formulations are the most promising, and that they could be available soon with increased industry commitment.
“Male contraception: A realistic option?”
Wenk M, Nieschlag E.
Eur J Contracept Reprod Health Care. 2006 Jun;11(2):69-80.
PMID: 16854679
Review of 8 trials for the impact of testosterone on bone density in hypogonadal men. Intramuscular forms of T “moderately increased lumbar bone density,” but the authors conclude that without bone fracture data for all subjects, “the available trials offer weak and indirect inferences about the clinical efficacy of testosterone on osteoporosis prevention and treatment in men.”
“Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials.”
Tracz MJ, Sideras K, Bolona ER, Haddad RM, Kennedy CC, Uraga MV, Caples SM, Erwin PJ, Montori VM.
J Clin Endocrinol Metab. 2006 Jun;91(6):2011-6. Epub 2006 May 23. Review.
PMID: 16720668
Motility targets
This study characterizes the location, subunit affinity and isoform expression of this enzyme in human spermatozoa. “Na,K-ATPase human α4 isoform has distinct functional properties and plays a primary role in sperm flagellar motility… The relevance of α4 in sperm motility provides the impetus for the search of specific α4 inhibitors that could be used as male contraceptives.”
“The Na,K-ATPase {alpha}4 isoform from humans has distinct enzymatic properties and is important for sperm motility.”
Sanchez G, Nguyen AN, Timmerberg B, Tash JS, Blanco G.
Mol Hum Reprod. 2006 Jul 22; [Epub ahead of print]
PMID: 16861705
The previously reported novel, mouse testis-enriched receptor, guanylyl cyclase (mGC-G) has been localized “to the plasma membrane overlying the acrosome and midpiece of the flagellum in mature sperm.” The protein is partially lysed “during epididymal sperm transport, resulting in a smaller fragment tethered on the mature sperm surface.” Incubation with anti-mGC-G antibody resulted in reduced progressive motility.
“Localization and characterization of an orphan receptor, guanylyl cyclase-G, in mouse testis and sperm.”
Huang YH, Wei CC, Su YH, Wu BT, Ciou YY, Tu CF, Cooper TG, Yeung CH, Chu ST, Tsai MT, Yang RB.
Endocrinology. 2006 Jul 20; [Epub ahead of print]
PMID: 16857755
Previously reported sAC null male mice with low progressive motility sperm have been characterized as the result of “defective cAMP production prevent[ing] engagement of multiple components of capacitation…”
“Soluble adenylyl cyclase (sAC) is indispensable for sperm function and fertilization.”
Xie F, Garcia MA, Carlson AE, Schuh SM, Babcock DF, Jaiswal BS, Gossen JA, Esposito G, van Duin M, Conti M.
Dev Biol. 2006 Jun 7; [Epub ahead of print]
PMID: 16842770
Supporting research
“Minutes of the 14th European Workshop on Molecular & Cellular Endocrinology of the Testis.”
Gromoll J, Michel C, Kostova E, Tuttelmann F, Wistuba J, Yeung CH, Henke A, Stukenborg JB, Akinloye O, Nieschlag E.
Mol Cell Endocrinol. 2006 Jul 19; [Epub ahead of print] No abstract available.
PMID: 16859825
Report of the method used to produce Dazl knockdown Norway rats. Rats expressing Dazl-shRNA showed normal female fertility but male infertility. Male knockdown rats produced ~70% less Dazl protein than their wild type counterparts.
“Heritable and stable gene knockdown in rats.”
Dann CT, Alvarado AL, Hammer RE, Garbers DL.
Proc Natl Acad Sci U S A. 2006 Jul 14; [Epub ahead of print]
PMID: 16844779
“Thus far, a growing number of novel or known genes have been identified and characterized by microarray technology to be possibly correlated with male infertility in mice and humans, which could reveal novel candidates for both diagnosis and therapy.”
“Microarray technology offers a novel tool for the diagnosis and identification of therapeutic targets for male infertility.”
He Z, Chan WY, Dym M.
Reproduction. 2006 Jul;132(1):11-9.
PMID: 16816329
“Inhibitors protein disulfide isomerase (PDI) activity were able to inhibit sperm-egg fusion in vitro. While pretreatment of oocytes had no effect, pretreatment of sperm reduced their fusion ability.”
“A role for sperm surface protein disulfide isomerase activity in gamete fusion: evidence for the participation of ERp57.”
Ellerman DA, Myles DG, Primakoff P.
Dev Cell. 2006 Jun;10(6):831-7.
PMID: 16740484
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The Endocrine Society held their 88th annual meeting, ENDO 2006, in Boston at the end of June. All ENDO 2006 abstracts are now available online. Dr. Michael Griswold of Washington State University summarized work on transcriptional profiling of the murine testis. “Databases have been created that portray the level at which tens of thousands of genes are expressed in the murine testis from the formation of the testis in the embryo through the onset of sperm production… The use of these extensive databases in conjunction with expression data from individual isolated cell types has provided information on the nature of genes expressed in a cell specific manner or expressed sequentially during a developmental process… The compilation of such gene expression data should provide insight into potential targets for contraception as well as focus future work on idiopathic infertility.”
Also in Boston, Dr. Chawnshang Chang and colleagues of the University of Rochester Medical Center presented their work on tissue-specific androgen receptor (AR) knock-out mice. In Sertoli (S-AR-/y) and Leydig (L-AR-/y) cell AR knock-outs, they observed spermatogenic arrest. “The testicular histology of 10 week old [general] AR-/y mice showed no lumen formation in seminiferous tubules and germ cell development stopped at pachytene primary spermatocytes; S-AR-/y mice showed no lumen formation and germ cell development stopped at pachytene/diplotene primary spermatocyte; L-AR-/y mice showed no lumen formation in seminiferous tubules and germ cell development stopped at round spermatid… These results clearly demonstrated that AR in different testicular cell types have different roles. ”
The 4th European Congress on Reproductive Immunology was held in Graz, Austria, during the second week of July. The full Congress proceedings were published in the July issue of the American Journal of Reproductive Immunology. Drs. John Herr and Young-hwan Kim of the University of Virginia spoke about their identification of glycolysis and energy transfer mechanisms in the flagellar fibrous sheath of human sperm. They found both somatic (aldolase A, triose phosphate isomerase, and pyruvate kinase) and testis-specific (lactate dehydrogenase C) forms of glycolytic enzymes. They also isolated a novel, testis-specific ADP/ATP translocase in the adenosine nucleotide translocase family, “sperm flagella energy carrier (SFEC).” They hypothesize that SFEC“ serves as an ATP intermediate in the flagellum possibly involving ATP storage or translocation to dynein ATPases. This suggests SFEC may serve as a key link between energy production, transport, and motility in the distal flagella.”
Also in Graz, Dr. Peter Johnson from the University of Liverpool and colleagues presented work on the role of the CD46 surface complement regulatory protein in sperm. CD46 “is expressed as an unusual molecular isoform on the acrosomal membrane of sperm, and becomes surface exposed only after the acrosome reaction (AR). Antibodies to the first short consensus repeat (SCR) domain of CD46, but not antibodies to the CD55 or CD59 CReg proteins, inhibit binding and penetration of zona-free eggs by human sperm. New World monkeys express a truncated CD46 isoform lacking SCR1 on all cells except sperm, supporting a role for the SCR1 ectodomain in fertilization.”
The Society for Reproduction and Fertility held their annual meeting in Leeds at the end of July. Dr. Peter O’Shaugnessy from the University of Glasgow spoke about the role of androgen receptors in murine testicular function. “Mice lacking FSH receptors have reduced testis size and sperm numbers but they are fertile. In contrast, in mice lacking androgen receptors spermatogenesis is arrested during meiosis indicating that androgen action is required for progression through this stage. Despite the clear, critical role for androgens in maintaining spermatogenesis little has been known until recently about the molecular mechanisms underlying androgen action on the Sertoli cell. Through use of microarrays and animal models of androgen insensitivity we are now, however, starting to identify targets of androgen action in the testis.”
Next month: Abstracts from the Society for the Study of Reproduction 39th Annual Meeting
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Here’s a chance to work together on raising male contraceptive research’s visibility! The Male Contraception Coaliton is creating a new website specifically for you, the research and policy community. The members-only site will include a contact directory, an annotated bibliography of peer-reviewed articles, and a presentation archive. The presentation archive will house text and graphics that are not traditionally published, such as Continuing Medical Education course syllabi, conference presentation slides and outlines.
By sharing your PowerPoints and presentations, you not only make sure colleagues are up to date on your work, you help colleagues raise the profile of the field in general. We are all busy; why reinvent the wheel each time we do a presentation? Take advantage of shared statistics and graphics to convincingly convey your message, and make sure your research or perspective is included in the Continuing Medical Education course that may grow out of this presentation library.
Send the text and graphics you would like to share with your colleagues to coalition@malecontraceptives.org.
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Antares Pharma has entered a joint development agreement with the Population Council for Nestorone gel contraceptive products. The Council has developed and holds the patent on Nestorone. Antares brings their “proprietary, advanced transdermal delivery (ATD™) gel platform” to the table. “Nestorone is a fourth-generation synthetic progestin contraceptive that has a good safety profile. It is not active when administered orally and is therefore especially appropriate for topical application… Certain hormonal contraceptives developed under this agreement could also possibly be effective as male contraceptive products.”
Indeed, Nestorone has been assessed for use in a transdermal male contraceptive regimen. Researchers at the University of Washington and Harbor UCLA Medical Center measured the extent of gonadotropin suppression in healthy men receiving daily doses of Testim and Nestorone gels. “The steady-state delivery of a progestin and an androgen by transdermal gel application would be a user-friendly delivery method as compared to injectable or implant approaches. Nestorone is a synthetic progestin that does not have any androgenic and estrogenic activity and is not expected to have some of the undesirable side effects of other drugs.” The researchers completed their last follow-up visits with trial volunteers in June and are now preparing to publish their results.
Read more about the Antares Pharma - Population Council agreement.
Read the clinical trial announcement for the UW/HUMC Testim + Nestorone trial.
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The periodical associated with Dr. Bob Hatcher et al.'s Contraceptive Technology book, the Contraceptive Technology Update newsletter, features an article about emerging male contraceptives in their now-available September issue. If you subscribe to the newsletter, look for “New compounds eyed for male contraception.”
Not just a female problem
by Georgie Binks , CBC News Viewpoint, 28 July
“Pregnancy should be a big worry for males these days, because the law has made them financially responsible for their children financially, but the condom or a vasectomy are still the only two birth control options available to men.”
NIH Prepares for a Lean Budget
by Jennifer Couzin , ScienceNOW Daily News, 19 July
“Yesterday, a Senate spending panel recommended a modest 0.7% increase, to $28.5 billion, for the fiscal year starting 1 October. While that's $200 million more than President George W. Bush requested and what a House spending panel approved last month, it's far less than biomedical researchers were expecting this spring after the Senate resolved to boost spending on health and education by $7 billion.”
Waiting for a male Pill: Complacency blamed for men's inadequate birth control options
by Jennifer Laliberté , National Review of Medicine, 15 June
“Your male patients are ready to give the 'male Pill' a shot and their female partners feel long overdue for a contraception vacation. Fears about permanent infertility have even been laid to rest by a large scale review in the April 29 issue of The Lancet which found that men stopped 'shooting blanks' after they went off the birth control. But still you have nothing to offer them. What's the holdup?”
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