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.

Zona pellucida binding targets
Identification of “over 100 proteins that are expressed on mature sperm at the site of sperm-oocyte interactions… Of the proteins we identified for which a gene knockout has been tested, a third have been shown to be essential for efficient reproduction in vivo… Twenty-five percent of the cell surface fraction proteins are previously uncharacterized. We have shown that at least two of these novel proteins are localized to the sperm head.”
“Proteomic analysis of sperm regions that mediate sperm-egg interactions.”
Stein KK, Go JC, Lane WS, Primakoff P, Myles DG.
Proteomics. 2006 Jun;6(12):3533-43.
PMID: 16758446 

“ERp57 is a reasonable candidate enzyme for disulfide isomerase activity during [mouse sperm-egg] fusion.” The incomplete “inhibition of gamete fusion observed in the presence of anti-ERp57 antibody… might be because the function-blocking activity of the anti-ERp57 antibody is not very high, or because additional proteins are involved in the process.”
“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

Capacitation targets
Ornidazole, an antibacterial drug used to treat amoebic dysentery, “affects the onset and progression of hamster sperm hyperactivation, capacitation associated protein tyrosine phosphorylation and acrosome reaction.”
“Antimicrobial drug ornidazole inhibits hamster sperm capacitation, in vitro.”
Siva AB, Yeung CH, Cooper TG, Shivaji S.
Reprod Toxicol. 2006 Jun 13; [Epub ahead of print]
PMID: 16777375

Interrelationship of protein kinase A and C activity to phosphatidylinositol-3 and 4-kinase activity.
“Sperm capacitation is regulated by the crosstalk between protein kinase A and C.”
Breitbart H, Rubinstein S, Etkovitz N.
Mol Cell Endocrinol. 2006 Jun 27;252(1-2):247-9. Epub 2006 Apr 27.
PMID: 16647197

Endocrine approaches
“Current combinations of T and progestogens completely suppress spermatogenesis without severe side effects in 80-90% of men, with significant suppression in the remainder of individuals.”
“Male hormonal contraceptives.”
Amory JK .
Minerva Ginecol . 2006 Jun;58(3):215-26.
PMID: 16783293

A study identifying both isoforms of the progesterone receptor genes using immunohistochemistry, Western blot and RT-PCR. The receptors were expressed in “the hypothalamus and the pituitary gland…, the mammary gland and some organs of the male genital tract – including the prostate and the epididymis – while the presence of the genomic PR in the testis was rather weak.”
“Tissue expression of the nuclear progesterone receptor in male non-human primates and men.”
Luetjens CM, Didolkar A, Kliesch S, Paulus W, Jeibmann A, Bocker W, Nieschlag E, Simoni M.
J Endocrinol. 2006 Jun;189(3):529-39.
PMID: 16731784

Cell adhesion targets
Quantification of the weakening of the actin based cell-cell adherens junction between Sertoli and germ cells in adjudin-treated rat testes.
“The Sertoli-spermatid junctional complex adhesion strength is affected in vitro by Adjudin.”
Wolski KM, Mruk DD, Cameron DF.
J Androl. 2006 Jun 28; [Epub ahead of print]
PMID: 16809272

Heat-based approaches
“Intermittent scrotal insulation affected not only the motility of the freshly collected sperm, but also their ability to withstand the additional stress of storage. The additional data on motility characteristics obtained by CASA appeared to be no more sensitive an indicator than the [manually counted] percentage of motile cells…”
“Ram sperm motility after intermittent scrotal insulation evaluated by manual and computer-assisted methods.”
Arman C, Quintana Casares PI, Sanchez-Partida LG, Setchell BP.
Asian J Androl. 2006 Jul;8(4):411-8.
PMID: 16763716

Genomic research
Four separate groups of researchers reported this month on the identification of small RNAs specific to mouse testes. The proteins, Piwi-interacting RNAs (piRNAs), are primarily expressed in developing spermatids. Orthologous proteins are found in zebrafish, rats and humans. “Given the timing of the maturational arrest in mili and miwi knockout mice at the pachytene spermatocyte and the spermatid steps, respectively, it is conceivable that piRNAs and germline-specific Piwi proteins regulate the timing of meiotic and post meiotic events through transcriptional and translational repression.”

“A germline-specific class of small RNAs binds mammalian Piwi proteins.”
Girard A, Sachidanandam R , Hannon GJ, Carmell MA.
Nature. 2006 Jun 4; [Epub ahead of print]
PMID: 16751776

“A novel class of small RNAs bind to MILI protein in mouse testes.”
Aravin A, Gaidatzis D, Pfeffer S, Lagos-Quintana M, Landgraf P, Iovino N, Morris P, Brownstein MJ, Kuramochi-Miyagawa S, Nakano T, Chien M, Russo JJ, Ju J, Sheridan R, Sander C, Zavolan M, Tuschl T.
Nature. 2006 Jun 4; [Epub ahead of print]
PMID: 16751777

“A novel class of small RNAs in mouse spermatogenic cells.”
Grivna ST , Beyret E, Wang Z, Lin H.
Genes Dev. 2006 Jul 1;20(13):1709-1714. Epub 2006 Jun 9.
PMID: 16766680

“Identification and characterization of two novel classes of small RNAs in the mouse germline: retrotransposon-derived siRNAs in oocytes and germline small RNAs in testes.”
Watanabe T, Takeda A, Tsukiyama T, Mise K, Okuno T, Sasaki H, Minami N, Imai H.
Genes Dev. 2006 Jul 1;20(13):1732-1743. Epub 2006 Jun 9.
PMID: 16766679 

“Bgr mRNA is most abundant in germ cells and Sertoli cells of adult mouse testes but also detectable in Leydig cells, implying that BGR/Bgr might be involved in the late stages of spermatogenesis. This conclusion is substantiated by the fact that the Bgr mRNA could not be detected until postnatal week three, when spermatogenesis starts in murine testis.”
“A novel mammalian bubblegum-related acyl-CoA synthetase restricted to testes and possibly involved in spermatogenesis.”
Fraisl P, Tanaka H, Forss-Petter S, Lassmann H, Nishimune Y, Berger J.
Arch Biochem Biophys. 2006 Jul 1;451(1):23-33. Epub 2006 May 8.
PMID: 16762313

“Our real-time polymerase chain reaction analysis indicated that the mRNA of human [testis specific protein 1] was expressed at significantly lower levels in motility-impaired patients.”
“Human testis specific protein 1 expression in human spermatogenesis and involvement in the pathogenesis of male infertility.”
Du Y, Huang X, Li J, Hu Y, Zhou Z, Sha J.
Fertil Steril . 2006 Jun;85(6):1852-4.
PMID: 16759931

Supporting research
A summary of the known effects of mutations in gonadotropins and their receptors on pubertal timing and reproductive phenotypes.
“Mutations along the pituitary-gonadal axis affecting sexual maturation: Novel information from transgenic and knockout mice.”
Huhtaniemi I.
Mol Cell Endocrinol. 2006 May 26; [Epub ahead of print]
PMID: 16730882

Proposes temperature-gated ion channels on flagellar and acrosomal membranes as a mechanism of sperms’ ability to gauge very slight changes in temperature.
“Sperm thermotaxis.”
Bahat A, Eisenbach M .
Mol Cell Endocrinol. 2006 Jun 27;252(1-2):115-9. Epub 2006 May 2.
PMID: 16672171

A study of a non-clinical population which used CASA to show “that as men age, they produce fewer motile sperm, which are able to travel less along a linear path, thus covering less forward distance per unit time.”
“Quantitative effects of male age on sperm motion.”
Sloter E, Schmid TE, Marchetti F, Eskenazi B, Nath J, Wyrobek AJ.
Hum Reprod. 2006 Jun 22; [Epub ahead of print]
PMID: 16793993

“[Ejaculated] sperm are transciptionally and translationally quiescent, and they can be successfully capacitated in vitro without any hormone and cytokine/growth factors.” Sperm cell receptors’ “in vivo physiological relevance needs to be carefully examined…”
“Receptors in Spermatozoa: Are They real?”
Naz RK, Sellamuthu R.
J Androl. 2006 Jun 28; [Epub ahead of print]
PMID: 16751618

Dysfunctional expression of the heat shock factor A2 gene is correlated with idiopathic oligoteratozoospermia.
“Oligozoospermia and heat-shock protein expression in ejaculated spermatozoa.”
Cedenho AP, Lima SB, Cenedeze MA, Spaine DM, Ortiz V, Oehninger S.
Hum Reprod. 2006 Jul;21(7):1791-1794. Epub 2006 Mar 3.
PMID: 16517558

Six genes critical for in vitro spermatogonial stem cell maintenance are regulated by glial cell line-derived neurotrophic factor. Male KO mice of the most responsive gene showed 25% decrease in spermatogenesis.
“Identifying genes important for spermatogonial stem cell self-renewal and survival.”
Oatley JM, Avarbock MR, Telaranta AI, Fearon DT, Brinster RL.
Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9524-9. Epub 2006 Jun 1.
PMID: 16740658

Comment on Oatley, et al. and thoughts on Drosophila versus mammalian stem cell niches.
“Glial cell line-derived neurotrophic factor maintains a POZ-itive influence on stem cells.”
Payne C, Braun RE.
Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9751-2. Epub 2006 Jun 19.
PMID: 16785424

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Abstracts from the 22nd Annual Meeting of the ESHRE

The June issue of Human Reproduction features a supplement (Volume 21, Supplement 1) dedicated to the “Abstracts of the 22nd Annual Meeting of the ESHRE”. The European Society of Human Reproduction and Embryology met in Prague during June of 2006. Although the bulk of the abstracts focus on various assisted reproductive technologies, there are also basic science abstracts about male fertility presented.

Expression of active forms of interleukin-18 family in testicular tissues and cells
M AbuElhija, E Lunenfeld, T Eldar-Geva, I Spitz, G Potashnik, and M Huleihel of Ben Gurion University, Soroka University Medical Center, and Shaare Zedeek Medical Center, Israel

“IL-18 is a multifunctional cytokine… secreted by monocytes, keratinocytes and epithelial cells following immune stimulation. IL-18 belongs to the IL-1 family, since it is structurally similar to IL-1b, and cleaved to its active form by the same enzyme, IL-1b-converting enzyme (caspase-1). It is involved in the regulation of T helper type 1 response. Recently, we have shown that IL-18 and its natural inhibitor [IL-18 binding protein (IL-18 BP)] are produced by testicular tissues and interstitial cells and germ cells. Their levels were increased following in vivo stimulation with LPS or stimulation of Leydig cells in vitro with LH or LPS. IL-18 was shown to decrease the capacity of LH-induced Leydig cells to secrete testosterone… This is the first study demonstrating the expression and the presence of active forms of IL-18 family in mouse testicular tissues and cells. IL-18 family could be involved in the regulation of steroidogenesis and the spermatogenic process under physiological and pathological conditions.”

In vitro effect of levonorgestrel on human sperm function
MJ Munuce, JA Nascimento, G Rosano, A Faundes and L Bahamondes of the University of Rosario, Argentina, and the University of Campinas, Brazil

“The levonorgestrel-releasing intrauterine system (LNG-IUS) exerts its contraceptive effect by interfering with sperm transport, ovulation and fertilization. However, a direct effect of the steroid on sperm function cannot be discarded. The aim of this study was to evaluate whether LNG, at doses comparable to that measured in the uterus during the use of the LNG-IUS, affects the detection of D-mannose-binding sites or zona pellucida (ZP) receptors on human spermatozoa. The association with acrosomal status was also investigated… in vitro exposure of capacitated spermatozoa to the assayed doses of LNG increased the proportion of spermatozoa with fewer chances of interacting with the ZP. Further studies should be carried out to confirm whether this mechanism is part of the contraceptive action of the LNG-IUS.”

Increased sperm ubiquitination correlates with routine semen analysis parameters
M Hodjat, MR Sadeghi, M Akhondi and M Ghaffari of the Reproductive Biotechnology Avesina Research Center, Iran

“Ubiquitin, a 8.5 kDa peptide that marks other proteins for proteasomal degradation, tags defective sperm during epididymal passage. Most of the ubiquitinated sperm are subsequently phagocytosed by the epididymal epithelium. A portion of defective sperm escapes phagocytosis and can be found in the ejaculate. Thus, sperm ubiquitination seems to be a universal marker for sperm defects, and can be used as a sperm function test… Increased sperm ubiquitination was inversely associated with good quality semen parameters such as normal morphology, sperm vitality, progressive motility and sperm concentration which support the use of ubiquitin as a biomarker of human sperm quality.”

Selecting and propagating spermatogonial stem cells in a serum-free medium
N Tanaka, QV Neri, T Takeuchi, Z Rosenwaks and GD Palermo of Cornell University, New York

“In mammals, millions of spermatozoa are produced daily, ultimately from spermatogonial stem cells (SSCs) in the testis. These precursors of spermatogonia depend for the survival and proliferation on specific growth factors. In addition, their adhesion to enveloping presumptive Sertoli cells seems to be crucial in preventing apoptosis of germ cells isolated from other cell contacts… Although enrichment and isolation of SSCs was successful, they proliferated on feeder cells only for a few days. On the other hand, the testicular somatic cells provided a tridimensional support system that ensured the proliferation of germ cells during extended in vitro culture, probably due to a variety of as yet unknown factors (necessary for SSC survival and proliferation). PGCs or gonocytes drive the migration and proliferation of somatic cells which then envelop them in a cellular architecture similar to that of sex cords.”

Next month: Abstracts from the Endocrine Society’s 88 th annual meeting, ENDO 2006

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Resources: NICHD’s Reproductive Tissue Sample Repository (RTSaR)

“The Reproductive Tissue Sample Repository (RTSaR) is a virtual repository with online tissue sample acquisition capabilities. The RTSaR provides investigators with real-time access to human and nonhuman primate tissue and fluid inventories from four tissue bank facilities that are supported through the Specialized Cooperative Centers Program in Reproduction Research. The tissue banks are located at the University of California, San Diego (human ovary bank), Stanford University (human endometrium and DNA bank), Johns Hopkins University (male reproductive tissues and fluids), and the Oregon National Primate Research Center (nonhuman primate tissues). The web site for the RTSaR is https://rtsar.nichd.nih.gov/rtsar/login. If you wish to access the RTSaR, you can request an id and password to access the system by contacting the network administrator at RTSaR@mail.nih.gov. Once you access the system, contact information for each bank is provided. Access is open to all investigators living in North America who are supported by research and research training grants from the NIH. One id and password will be provided to each principal investigator that can be utilized by any person working in the P.I.’s laboratory, or, in the case of institutional training grants (T32) and institutional career development award programs (K12), any person supported by the aforementioned awards.”

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Male contraceptives in the popular press

Below are some examples of popular press coverage during the last month. 

New male contraceptives show promise (14 June, ScienceDirect and FOX News)
“Several new male contraceptives that kill sperm, block sperm production or prevent sperm from leaving the body have recently begun clinical trials…” An accurate and readable report on male hormonal contraception, the US design of the Intra Vas Device and RISUG.

The June issue of Glamour magazine featured a piece on the development of RISUG.

China conducts research on side-effects of contraceptives (22 June, Xinhua news agency)
Several hundred thousand men in China with various vas-blocking contraceptive devices should be included in this nation-wide survey of contraceptive safety and efficacy.

Mice testicles reveal new class of RNAs (4 June, Nature magazine)
The two articles published this month about newly-discovered small RNAs in mouse germ cells resulted in a Nature news piece.

Articles like these are putting male contraception on the radar of policymakers and federal funding agencies. Make sure that your work stays in the limelight by keeping the Male Contraception Information Project informed when you have news! MCIP interacts regularly with the press and can even 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.

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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!

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 14	Royal Society of Medicine’s Key Advances in the clinical management of contraception and sexual health; London, UK
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. MCC and MCIP will have a booth... Come say hello!
September 17-22	10th International Symposium on Spermatology; Madrid, Spain
October 10-12	International Union for the Scientific Study of Population’s Seminar on the Ecology of the Male Life Course; near Marburg, Germany
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	28th 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 3-8	3o Encuentro iberoamericano de andrología; La Habana, Cuba
December 4-7	4th International Workshop on the Epididymis; Chatel-Guyon, France
December 8-10	4th 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