MALE CONTRACEPTION UPDATE

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.

The May issue of Molecular and Cellular Endocrinology (Volume 250, Issues 1-2, Pages 1-214, 16 May 2006) is entitled “Post-Meiotic Approaches to Male Contraception - Focusing on Potential Targets.” The issue is devoted to the work presented at the Symposium on Post-meiotic Approaches to Male Contraception in Hong Kong during June of 2005. In the preface, Dr. Ursula Habenicht of Schering AG writes: “The Second Meeting of the joint Rockefeller/Ernst Schering Network from which this publication originates has provided the occasion for experts in the field to share their views in light of their most recent findings and to put more focus into exploring the potentials in this area, particularly the novel ‘postmeiotic approaches’ of interfering with male fertility after the genesis of sperm.” A number of the articles in this issue were summarized in the April Male Contraception Update; several more are summarized this month.

Motility targets
Suggests that murine models are substantially homologous to human GAPD2, and “that reliable comparisons can be made between these species in toxicant screening and contraceptive development.”
“Expression of the spermatogenic cell-specific glyceraldehyde 3-phosphate dehydrogenase (GAPDS) in rat testis.”
Welch JE, Barbee RR, Magyar PL, Bunch DO, O'brien DA.
Mol Reprod Dev. 2006 May 14; [Epub ahead of print]
PMID: 16700075

GAPDS, aldolase 1A, lactate dehydrogenase A and pyruvate kinase are found on the surface of mouse sperm flagella. “These data support a role for the fibrous sheath as a scaffold for anchoring multiple glycolytic enzymes along the length of the flagellum to provide a localized source of ATP…”
“Multiple Glycolytic Enzymes are Tightly Bound to the Fibrous Sheath of Mouse Spermatozoa.”
Krisfalusi M , Miki K , Magyar PL , O'brien DA.
Biol Reprod. 2006 May 10; [Epub ahead of print]
PMID: 16687649

In vitro tests show that the n-butanol fraction of a native Indian plant halts goat and human sperm motility upon contact at a concentration of 400 micrograms/mL.
“Sperm motility inhibiting activity of a phytosterol from Alstonia macrophylla Wall ex A. DC . leaf extract: a tribal medicine.”
Chattopadhyay D, Dungdung SR, Das K, Saha S, Mandal AB, Majumder GC.
Indian J Exp Biol. 2005 Nov;43(11):1104-9.
PMID: 16313073

Three known isoforms of glycodelin inhibit sperm capacitation or zona pellucida binding, with glycodelin-S “abundant in the human seminal plasma.”
“Roles of glycodelin in modulating sperm function.”
Yeung WS, Lee KF, Koistinen R, Koistinen H, Seppala M, Ho PC, Chiu PC.
Mol Cell Endocrinol. 2006 May 16;250(1-2):149-56. Epub 2006 Jan 18.
PMID: 16413672

Epididymal targets
Using a method they describe as “fast, efficient, cheap and safe compared to other strategies such as viral infection or the creation of transgenic mouse lines,” this group has identified two potential contraceptive pathways in the epididymis: a 5-alpha-reductase inhibitor plus either a growth factor inhibitor or a drug promoting apoptosis.
“Identifying putative contraceptive targets by dissecting signal transduction networks in the epididymis using an in vivo electroporation (electrotransfer) approach.”
Fox SA, Yang L, Hinton BT.
Mol Cell Endocrinol. 2006 May 16;250(1-2):196-200. Epub 2006 Jan 19.
PMID: 16423449

Review of the glycohydrolases and glycosyltransferases present in epididymal luminal fluid and their possible roles in sperm maturation during epididymal transit.
“Glycan-modifying enzymes in luminal fluid of the mammalian epididymis: An overview of their potential role in sperm maturation.”
Tulsiani DR.
Mol Cell Endocrinol. 2006 May 16;250(1-2):58-65. Epub 2006 Jan 18.
PMID: 16413674

Reviews the balance of reactive oxygen species production and recycling in epididymal transit, with a focus on glutathione peroxidases, indolamine dioxygenase “expression presence and putative roles.”
“The antioxidant glutathione peroxidase family and spermatozoa: A complex story.”
Drevet JR.
Mol Cell Endocrinol. 2006 May 16;250(1-2):70-9. Epub 2006 Jan 19.
PMID: 16427183

Sperm adhesion molecule 1 is an androgen-regulated hyaluronidase with a specific form expressed in the epididymis of mice, rats, bulls, macaques and humans. In vitro uptake of epididymal SPAM1 (ES) “significantly increases the ability of null sperm to penetrate the cumulus of oocytes via hyaluronidase activity, directly relating ES uptake with fertilizing ability…”
“Epididymal SPAM1 and its impact on sperm function.”
Martin-Deleon PA.
Mol Cell Endocrinol. 2006 May 16;250(1-2):114-21. Epub 2006 Jan 18.
PMID: 16420970

Zona pellucida binding targets
Sperm surface receptors that mediate the initial binding of sperm to the zona pellucida are potential contraceptive targets. SED1 (a Secreted protein containing a cleavable signal sequence, N-terminal Notch-like type II EGF repeats and C-terminal Discoidin/F5/8 Complement domains), a receptor acquired during epididymal transit, is one such receptor.
“Identification of novel gamete receptors that mediate sperm adhesion to the egg coat.”
Shur BD, Rodeheffer C , Ensslin MA, Lyng R , Raymond A.
Mol Cell Endocrinol. 2006 May 16;250(1-2):137-48. Epub 2006 Jan 18.
PMID: 16417965

Endocrine approaches
Description of hypothalamic-pituitary-gonadal axis in luteinising hormone receptor null (LuRKO) and choriongonadotrophin over-expressing mice, including attempts to rescue the LuRKO hypogonadism. One of “the most intriguing [novel phenotypic features found was] the spermatogenic potential of the testis in the absence of LH stimulation and high intratesticular T…”
“Genetically modified mouse models in studies of luteinising hormone action.”
Huhtaniemi I, Ahtiainen P, Pakarainen T, Rulli SB, Zhang FP, Poutanen M.
Mol Cell Endocrinol. 2006 May 1; [Epub ahead of print]
PMID: 16675102

Three quarters of men participating in a clinical trial of an injectable male hormonal contraceptive lasting for one year rated the method acceptable, good or excellent. None of the men complained of side effects, but one third of them found the delivery method inconvenient. 94% of the men would pay 10 to 20 Euros per month for such a contraceptive.
“Acceptability of an injectable male contraceptive regimen of norethisterone enanthate and testosterone undecanoate for men.”
Meriggiola MC, Cerpolini S, Bremner WJ, Mbizvo MT, Vogelsong KM, Martorana G, Pelusi G.
Hum Reprod. 2006 May 26; [Epub ahead of print]
PMID: 16731547

Cell adhesion targets
Review of junction dynamics in the epithelial cells and in the testis, highlighting “the specific areas that require further research for a thorough understanding of the role of junction remodeling in spermatogenesis.”
“Regulation of junction dynamics in the testis-Transcriptional and post-translational regulations of cell junction proteins.”
Lui WY , Lee WM.
Mol Cell Endocrinol. 2006 May 16;250(1-2):25-35. Epub 2006 Jan 20.
PMID: 16431017

Supporting research
Dby (DEAD-box RNA helicase Y, also known as Ddx3y) in the mouse is not required for spermatogenesis, and therefore not functionally homologous to human DBY.
“Structural Characterization and Expression Studies of Dby and Its Homologs in the Mouse.”
Vong QP, Li Y, Lau YF, Dym M , Rennert OM , Chan WY.
J Androl. 2006 May 25; [Epub ahead of print]
PMID: 16728723

“A SAGE analysis of ejaculate from fertile men has revealed a large number of transcripts, which occur n steady frequencies and probably have important roles in spermatogenesis and fertilization.”
“Characterization and quantification of mRNA transcripts in ejaculated spermatozoa of fertile men by serial analysis of gene expression.”
Zhao Y, Li Q, Yao C, Wang Z, Zhou Y, Wang Y, Liu L, Wang Y, Wang L, Qiao Z.
Hum Reprod. 2006 Jun;21(6):1583-90. Epub 2006 Feb 24.
PMID: 16501037

Presence of adrenergic receptors which regulate cAMP production found in both mouse and human spermatozoa, “especially [in the] acrosomal and neck regions, and flagellum”. Activation of the receptors is “capacitation state-dependent and provide[s] a mechanism for inhibiting spontaneous acrosome reactions and helping to maintain fertilizing ability.”
“Identification of functional {alpha}2- and beta-adrenergic receptors in mammalian spermatozoa.”
Adeoya-Osiguwa SA, Gibbons R, Fraser LR.
Hum Reprod. 2006 Jun;21(6):1555-1563. Epub 2006 Feb 17.
PMID: 16488904

1 nmol/L genistein causes >30% of human sperm to undergo an acrosome reaction within 1 hour of in vitro exposure. The researchers propose that this is caused by the action of membrane-associated adenyl cyclases and call for an investigation of sperm plasma membrane estrogen receptors.
“Effects of estrogenic xenobiotics on human and mouse spermatozoa.”
Fraser LR, Beyret E, Milligan SR, Adeoya-Osiguwa SA.
Hum Reprod. 2006 May;21(5):1184-93. Epub 2006 Feb 3.
PMID: 16459350

CREB3L4 protein (cAMP responsive element binding protein 3-like 4) occurs “in post-meiotic spermatids in a stage-specific manner… These findings suggest that testis-specific isoforms of Creb3l4 could play an important role in spermatid differentiation.”
“Stage-specific expression of the Atce1/Tisp40{alpha} isoform of CREB3L4 in mouse spermatids.”
El-Alfy M, Azzi L, Lessard J, Lavergne E, Pelletier M, Labrie C.
J Androl. 2006 May 25; [Epub ahead of print]
PMID: 16728718

 

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Report from the 14th European Workshop on the Molecular and Cellular Endocrinology of the Testis

The biannual 14th European Testis Workshop (ETW) convened in Bad Aibling, Germany from 22-26 April 2006. Over 220 participants from 14 different European countries, as well as participants from North and South America, Australia and Japan attended the workshop, which was supported by the German Research Foundation. The ETW featured symposia on Mammalian Testis Biology, Endocrine Regulation of Spermatogenesis, Sperm Function, Contraception, Male Infertility, Germ Cell Potential and Disturbed Puberty. Very brief summaries of work related to male contraceptive research and development follow.

Highlights

• Jan Bogerd presented on the ligand-selective determinants of gonadotropin receptors. Deciphering of ligand selective determinants is important for our understanding of gonadotropin action.
• Katja Teerds outlined perspectives on Leydig cell research. She introduced recent findings on Leydig stem cells which will have major implications for understanding steroidogenesis and Leydig cell function.
• Jean-Pierre Dadoune gave a comprehensive overview of sperm RNA. Studies have revealed a rich repertoire of both known and unknown protein-encoding and non-encoding RNA species in sperm, including many transcripts from aromatase to SRY and for functional proteins, but the role of sperm RNA remains obscure.
• Hanns Hatt presented his work on olfactory receptors in sperm, in particular hOR17-4. Studies utilizing agonists and antagonists have demonstrated the role of hOR17-4 in chemotaxis, chemokinesis and hyperactivation. Ca2+ influx initiated by ligand activation of this G protein-coupled receptor may involve membrane adenylate cyclase (mACIII), activating cyclic nucleotide-gated Ca2+ channels.
• Serge Carreau emphasized the role of estrogens in spermatogenesis, the importance of cytochrome P450 for metabolism and activity of estrogens. He summarized the effects of estrogens on the different stages on spermatogenesis, such as proliferation of gonocytes, differentiation of round spermatids, acrosome formation, increasing sperm motility, control of spermatozoa-associated proteins in the epididymis, and as an anti-apoptotic factor in germ cells. He concluded that aromatase deficiency impaired sperm quality.
• Aarnould van der Spoel presented evidence from his studies showing that alkylated imino sugars can induce reversible infertility in male mice. Animals exposed to these agents showed no sign of spermatid development and impaired acrosomal development. He concluded that alkylated iminosugars have a long-term and reversible contraceptive effect on spermatogenesis and could serve as a tool for the development of a contraceptive.
• Matti Poutanen reviewed his search for novel targets for contraception in the epididymis, employing the expressed sequence tags (EST) technique to screen for novel genes. Among the novel promising target genes are Rnase 9 and 10. Both have ribonuclease activities, are anti-immunogenic, epididymis-specific, and segment-specific within the epididymis. Efforts are ongoing to produce knockout mice for functional validation of these genes.

The 15th European Testis Workshop will be held in Naantila, Finland, May 3 to 7, 2008.

Thank you to the authors of the ETW minutes which will be published in Molecular & Cellular Endocrinology, from which this report is excerpted: Drs. Jörg Gromoll, Caroline Michel, Elena Kostova, Frank Tüttelmann, Joachim Wistuba, Ching-Hei Yeung, Alexander Henke, Jan-Bernd Stukenborg, Oluyemi Akinloye and Eberhard Nieschlag .

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Abstracts from the 9th Congress of the European Society of Contraception

Improving quality of life through contraception health benefits
Elof Johansson, Population Council, New York, NY, USA
“The world in 2006 has 1,773 millions of young people age 10-24 years. This number of young people is 27% of world's population and the largest number of young people the world has ever seen. This youth cohort needs effective and safe contraceptives in order to get education and a place in society.”

Hormonal Contraception for men: Past and Future
Regine Sitruk-Ware, Rockefeller University and Population Council, New York, NY, USA
“Development of highly effective, practical, and acceptable non-traditional male contraceptives has proven to be a daunting challenge for more than three decades… Methods of fertility control in men that depend on the sustained suppression of gonadotropins will require the concomitant administration of an androgen as an essential part of the method. 7a-methyl-19-nortestosterone (MENT™) is a synthetic androgen that is more potent than T for gonadotropin suppression … MENT Acetate (MENT Ac) has diffusion characteristics that are well suited for delivery via subdermal implants, [and] is rapidly hydrolyzed in vivo to MENT, the biologically active molecule. MENT Ac implants administered once were able to suppress spermatogenesis to a degree comparable to those reported in studies with multiple injections of TE or testosterone undecanoate (TU) or with T implants in normal men. The prostate sparing effect of MENT has previously been shown in a study in castrated cynomolgus monkeys where the effect of MENT was directly compared with that of testosterone. Doses of MENT that will completely replace testosterone for its anabolic and antigonadotropic actions will be less stimulatory to the prostate. Hence the use of MENT in men over long-term is expected to have a health benefit.”

Hormonal contraception for men: Limitations
Eberhard Nieschlag, Institute of Reproductive Medicine of the University of Münster, (WHO Collaboration Centre for Research in Male Reproduction), Münster, Germany
“As opinion polls show, men are ready for hormonal male contraception… However, they would prefer a pill over any other mode of application. Notwithstanding, modalities for male contraception currently under investigation favor testosterone and gestagen injections or implants or a combination of both… This implies that the contraceptive will not be self administered, but will rather require medical assistance for initiation and possibly also for termination. The contraceptive protection provided by a hormonal male method will have a relatively slow onset [of 3 months]… Similarly, recovery of spermatogenesis after cessation of hormonal male contraception is relatively slow requiring 3-6 months… It is unclear whether use [longer than 1 year] may result in prolonged recovery phases. Non-uniformity of suppression of spermatogenesis remains an important limitation… Semen analysis [may] be required before contraceptive protection can be guaranteed. These investigations would complicate the use of a male hormonal contraceptive, but would be similar to the requirements after vasectomy.”

New approaches to contraception for men: do men and women want them?
Richard Anderson, Clinical Reproductive Science, Division of Reproduction and Developmental Science, University of Edinburgh, UK
“The development of the oral contraceptive pill enabled women for the first time to control their fertility safely and effectively… Male methods remain inconvenient, ineffective or irreversible. Despite this men are major users of contraception, and condoms [are] used by most couples at some point. The last 20 years have seen the slow development of hormonal-based methods for men… Men's attitudes and knowledge have been surveyed over many years, and have consistently demonstrated interest in the development of new methods. In one survey of 450 men in the UK , South Africa and China ( Shanghai and Hong Kong ), the majority of men welcomed a new hormonal method even though they were mostly happy with their existing method… A recent much larger survey (7000 participants from 9 countries) came to similar conclusions… Few studies have addressed [women’s attitudes], but the available data suggest that women in a variety of cultural settings feel that the responsibility for contraception should be shared more than at present, and a great majority supported the development of a 'male pill'. These surveys give a clear and consistent message that both men and women want to see new male methods become available.”

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Resources: the newly founded Society for Family Planning and Young Testis Club

In the June issue of Contraception, Dr. Philip Darney of UCSF announced a new non-profit organization dedicated to “bring[ing] together medical professionals who are interested in the scientific study of family planning” — the Society for Family Planning. It takes as its model the European Society of Contraception and aims to create a “proper forum for American researchers in family planning to share project ideas, form collaborations, review works in progress and critique assumptions and conclusions.” Dr. Darney writes: “we intend the Society to become the premier forum for presenting evidence from investigation in family planning, for educating new scholars, and for fostering fellowship in our discipline.” The Society for Family Planning will hold their meeting in conjunction with the Association of Reproductive Health Professionals’ meeting, “Reproductive Health 2006” in La Jolla, CA , from September 6-9.

Following the 14 th European Testis Workshop, a group of young researchers announced the founding of the Young Testis Club, whose aim is “to assist young scientists in testis research in achieving their highest potential as a researcher, and to stimulate good and efficient science in the field. The Young Testis Club is committed to establishing global networks between young (early stage) scientists in testicular research and to promote cooperation and mutual exchange of methodologies and expertise. Moreover, it provides a discussion forum for practical and theoretical problems.” The Club intends to organize annual meetings, which will coincide with the European Testis Workshop every other year.

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Male contraceptives in the popular press

The work of the male contraceptive research community is of increasing interest to the press. Below are some examples of popular press coverage during the last month. Articles like these are putting male contraception on the radar of policymakers and federal funding agencies. Keep their interest piqued by publicizing your work. If your organization does not have a press office, the Male Contraception Information Project will help you get your work in the news via the American Association for the Advancement of Science’s EurekAlert news press release service. For further information, contact Elaine Lissner.

The announcement of the US FDA’s approval of a trial of a new design of the intra vas device got good coverage in India and Australia:
Intra Vas Device: The New male contraceptive (6 May, RxPG News)

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Calendar of Events

Upcoming events in the andrology, infertility, endocrinology, contraceptive and family planning service provision communities. Planning an event? Let us know about it!

June 18-21	European Society of Human Reproduction and Embryology 22nd Annual Meeting; Prague, Czech Republic
June 24-27	The Endocrine Society’s 88th Annual Meeting ENDO 2006; Boston, MA, US
June 30	Deadline for Asia-Pacific Forum on Andrology abstract submission
July 3-5	Society for Reproduction and Fertility 2006 Annual Conference; Leeds, West Yorkshire, UK
July 5-9	4th European Congress of Reproductive Immunology; Graz, Austria
July 14	Deadline for European Congress of Andrology abstract submission
July 29 - Aug 1	Society for the Study of Reproduction 39th Annual Meeting; Omaha, NB, US
August 31	Deadline for British Andrology Society Annual Meeting abstract submission
September 7-10	Association of Reproductive Health Professionals 2006 Annual Meeting; La Jolla, CA, US
September 17-22	10th International Symposium on Spermatology; Madrid, Spain
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 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 5-8	3rd International Conference on Experimental and Clinical Reproductive Immunology; Banff, British Columbia, Canada
November 11-14	American Medical Association House of Delegates Interim meeting; Las Vegas, NV, US
November 12-16	28 th Congress of the Societe Internationale d’Urologie; Cape Town, South Africa
November 16-18	British Andrology Society Annual Meeting on sperm function and maturation; Leeds, UK
December 4-7	Fourth International Workshop on the Epididymis; Chatel-Guyon, France
December 8-10	Fourth European Congress of Andrology; Toulouse, France

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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