MALE CONTRACEPTION UPDATE

Summaries of new peer-reviewed publications

Sperm-egg fusion targets
Review of known sperm- and oocyte-surface proteins which are “essential for gamete fusion.” The letter describes Izumo, and asks whether gamete fusion will share conserved elements of virus-host or intracellular membrane fusion. It summarizes: “Now that so much is known about virus-cell and intracellular fusion, cell-cell fusion may become a new frontier.” As most of the identified fusion-related proteins have unknown functions, “this area seems very open to new hypotheses, results and understanding.”
Cell-cell membrane fusion during mammalian fertilization.
Primakoff P, Myles DG.
FEBS Lett. 2007 Feb 20; [Epub ahead of print]
PMID: 17328899

“The immunoglobulin superfamily protein IZUMO on the sperm surface was identified as being essential for sperm-egg fusion.” In a small study of infertile male patients with severe oligozoospermia, none of the men were IZUMO negative according to immunocytochemistry.
Positive expression of the immunoglobulin superfamily protein IZUMO on human sperm of severe male infertile patients.
Hayasaka S, Terada Y, Inoue N, Okabe M, Yaegashi N, Okamura K.
Fertil Steril. 2007 Feb 9; [Epub ahead of print]
PMID: 17296188

“Tetraspanin CD81 is closely homologous in amino acid sequence with CD9… [which] is well known to be involved in sperm-egg fusion, and CD81 has also been reported to be involved in membrane fusion events.” In CD81 null mice, “eggs had [an] impaired ability to fuse with sperm… [which] may be in part caused by failure of the acrosome reaction of sperm.”
Possible involvement of CD81 in acrosome reaction of sperm in mice.
Tanigawa M, Miyamoto K, Kobayashi S, Sato M, Akutsu H, Okabe M, Mekada E, Sakakibara K, Miyado M, Umezawa A, Miyado K.
Mol Reprod Dev. 2007 Feb 8; [Epub ahead of print]
PMID: 17290409 

Endocrinological approaches
A new theory of male hormonal contraceptive (MHC) non-responders: “Since insulin-like factor-3 (INSL3) has been shown to prevent germ cell apoptosis in mice, we hypothesized that INSL3 might be higher in men with persistent spermatogenesis during treatment with MHCs… After six months of treatment with a MHC regimen, higher serum INSL3 concentrations are associated with persistent sperm production. INSL3 may play a role in preventing complete suppression of spermatogenesis in some men on MHC regimens. This finding suggests that INSL3 could be a potential target for male contraceptive development.”
Elevated end-of-treatment serum INSL3 is associated with failure to completely suppress spermatogenesis in men receiving male hormonal contraception.
Amory JK, Page ST, Anawalt BD, Coviello AD, Matsumoto AM, Bremner WJ.
J Androl. 2007 Feb 21; [Epub ahead of print]
PMID: 17314233

5α-reductase inhibitors dutasteride and finasteride significantly suppressed serum DHT and transiently increased serum T. Both treatments caused a transient decrease in total sperm count and motility. Only dutasteride caused a significant decrease in semen volume. Neither sperm concentration nor morphology w as significantly affected. “This study demonstrates that the decrease in DHT induced by 5ARIs is associated with mild decreases in semen parameters that appear reversible after discontinuation.”
The Effect of 5{alpha}-Reductase Inhibition with Dutasteride and Finasteride on Semen Parameters and Serum Hormones in Healthy Men.
Amory JK, Wang C, Swerdloff RS, Anawalt BD, Matsumoto AM, Bremner WJ, Walker SE, Haberer LJ, Clark RV.
J Clin Endocrinol Metab. 2007 Feb 13; [Epub ahead of print]
PMID: 17299062

Supporting endocrinological research
“[These] results indicate that inhibition of the mitochondrial electron transport chain can block LH-stimulated testosterone production through suppression of a number of steps of the steroidogenic pathway, but also stimulates basal testosterone production through a calcium-mediated mechanism.”
Effect of Myxothiazol on Leydig Cell Steroidogenesis: Inhibition of LH-Mediated Testosterone Synthesis But Stimulation of Basal Steroidogenesis.
Midzak AS, Liu J, Zirkin BR, Chen H.
Endocrinology. 2007 Mar 1; [Epub ahead of print]
PMID: 17332065

A summary of what is known to date about tissue-selective androgen receptor modulators. “The concept of a SARM was documented first in 1999, and the aryl propionamide SARMs were the first to demonstrate tissue selectivity in vivo in 2003, followed later that year by a tetrahydroquinoline (THQ) SARM, and quinoline SARMs in 2006. Most of [the] current research efforts have focused on the development of non-steroidal AR agonists as tissue-selective agents, but there is also interest in developing [a] tissue-selective AR antagonist, and steroidal SARMs… Because each of these lead compounds [see table] is orally available and tissue selective in vivo, their potential applications in treatment have been assessed using various animal models, including muscle wasting (LGD2226, S4 and BMS56929), osteoporosis (LGD2226, S4 and S-40503), male contraception (C6) and BPH (S1). Although the mechanisms of action of these ligands have not been investigated fully, available data indicate that the tissue-specific expression of 5α-reductase contributes, at least partially, to the tissue selectivity of these ligands.”

Chemotype	General chemical structure	Lead compound	Compound chemical structure
Quinolinone analogs		LGD2226
Aryl propionamide analogs		S4
		S1
		C6
Hydantoin analogs		BMS564929
Tetrahydro-quinoline analogs		S40503

Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs).
Gao W, Dalton JT.
Drug Discov Today. 2007 Mar;12(5-6):241-8. Epub 2007 Feb 7.
PMID: 17331889

A look at one of the intra-testicular mediators of spermatogenesis: Galectin-3 (Gal-3). Gal-3 is found in the Sertoli cell cytoplasm of human, rat and porcine testes, where it is mediated by FSH, EGF and TNF-α, and possibly directly by the maturing germ cells. Although its function is unknown, a “potential role of Gal-3 in germ cell survival/regeneration is suggested based on its increased expression 1 month after a transient germ cell death [processes] triggered by 10 days treatment with the antiandrogen fluamide.”
Expression of galectin-3 and its regulation in the testes.
Deschildre C, Ji JW, Chater S, Dacheux F, Selva J, Albert M, Bailly M, Hatey F, Benahmed M.
Int J Androl. 2007 Feb;30(1):28-40. Epub 2006 Nov 27.
PMID: 17132155

Motility targets
Intraflagellar transport protein 46 (IFT46) “is a highly conserved complex B protein in both [the green alga Chlamydomonas reinhardtii and mice].” In general IFTs are “involved in the turnover of flagellar components, in the movement of flagellar membrane components in the plane of the membrane, and in cilium- generated signaling. Consequently, mutations in IFT affect ciliary and flagellar assembly, maintenance, and function… In addition to being very short, ift46 flagella have defects in central pair and dynein arm assembly. Aspects of this phenotype are undoubtedly caused by the greatly reduced amount of complex B in the ift46 mutant.”
Functional analysis of an individual IFT protein: IFT46 is required for transport of outer dynein arms into flagella.
Hou Y, Qin H, Follit JA, Pazour GJ, Rosenbaum JL, Witman GB.
J Cell Biol. 2007 Feb 26;176(5):653-65. Epub 2007 Feb 20.
PMID: 17312020 

Cell adhesion targets
“The GTPase Rap1 serves as a critical point in signal transduction, somatic cell proliferation and differentiation, and cell-cell adhesion acting through distinct mechanisms.” In Rap1-deficient male mice, they observed “a derailment of spermiogenesis due to an anomalous release of immature round spermatids from the seminiferous epithelium within the tubule lumen and low sperm counts.” The mutant male mice “exhibited perturbations in ectoplasmic specializations (ES), a Sertoli/germ cell-specific adherens junction… We found that germ cells express VE-cadherin with a timing strictly related to apical ES formation and function: immature, VE-cadherin positive spermatids were however prematurely released…”
Impaired Fertility and Spermiogenetic Disorders with Loss of Cell Adhesion in Male Mice Expressing an Interfering Rap1 Mutant.
Aivatiadou E, Mattei E, Ceriani M, Tilia L, Berruti G.
Mol Biol Cell. 2007 Feb 21; [Epub ahead of print]
PMID: 17314400 

“Cadhereins are Ca(2+)-dependent transmembrane proteins that mediate cell-cell adhesion. The aim of this study was to compare the expression of P-cadherin in unilaterally cryptorchid and busulphan-treated rat testes using immunohistochemistry… The membranes of round spermatids and membranes and cytoplasm of spermatocytes were strongly positive.” Busulphan treatment and cryptorchism “led to destructive changes in the structure of the seminiferous tubules, together with the decrease in P-cadherin expression… We suggest that P-cadherin participates in the architecture of adherens junctions in testis, plays an important role in maintaining normal spermatogenesis and that cryptorchism and busulphan treatment lead to adherens junction disintegration.”
Changes in the expression of P-cadherin in the normal, cryptorchid and busulphan-treated rat testis.
Pospechova K, Kopecky M, Nachtigal P, Pospisilova N, Jamborova G, Semecky V.
Int J Androl. 2007 Feb 12; [Epub ahead of print]
PMID: 17298545 

Supporting proteomic/genomic research
“Members of the dual specificity tyrosine phosphorylated and regulated kinase family (Dyrk) were shown to have a highly testis-abundant or testis-restricted expression pattern… We identified Dyrk4 as a testis-specific kinase with a very restricted expression to stage VIII postmeiotic spermatids…[However,] analysis of a Dryk4 deficient mouse line showed that Dyrk4 is dispensable for male fertility, hence suggesting a functional redundancy of some Dyrk isoforms during spermiogenesis.”
The expression of the testis-specific Dyrk4 kinase is highly restricted to step 8 spermatids but is not required for male fertility in mice.
Sacher F, Moller C, Bone W, Gottwald U, Fritsch M.
Mol Cell Endocrinol. 2007 Jan 17; [Epub ahead of print]
PMID: 17292540

“The mouse retrogene Utp14b is essential for male fertility, and a mutation in its sequence results in the sterile juvenile spermatogonial depletion (jsd) phenotype… Utp14b (predominantly variant 1) is expressed at moderately high levels in pachytene spermatocytes,” and this paper offers an evolutionary theory of Utp14a and b’s germ cell specificity.
Utp14b: A unique retrogene within a gene that has acquired multiple promoters and a specific function in spermatogenesis.
Zhao M, Rohozinski J, Sharma M, Ju J, Braun RE, Bishop CE, Meistrich ML.
Dev Biol. 2007 Jan 9; [Epub ahead of print]
PMID: 17291484

A look at gene expression profiles which classifies them into several categories: “postmeiotically upregulated genes encoding various enzymes, structural and regulatory proteins, and chaperones, and downregulated genes encoding haemoglobins and oxidation/reduction-related proteins or the machinery associated with protein synthesis, such as ribosomal proteins.”
Comprehensive analysis of gene expression in testes producing haploid germ cells using DNA microarray analysis.
Ike A, Tokuhiro K, Hirose M, Nozaki M, Nishimune Y, Tanaka H.
Int J Androl. 2007 Feb 12; [Epub ahead of print]
PMID: 17298544

“mUBPy is a deubiquitinating enzyme expressed preferentially in male germ cells and neurons… [and] interacts with the sperm-specific molecular chaperone MSJ-1 and associates with the proteasome [in mouse spermatozoa]… mUBPy and MSJ-1 label the cytoplasmic side of the acrosomal membrane and the centrosome… mUBPy is able to bind gamma-tubulin, a centrosomal protein marker.”
MUBPy is a novel centrosome-associated protein and interacts with gamma-tubulin.
Berruti G, Aivatiadou E.
J Submicrosc Cytol Pathol. 2006 Apr;38(1):77-83.
PMID: 17283968

Andrology training standards
The European Academy of Andrology (EAA) runs a training program for clinical andrologists consisting of two years in a training center and written and oral exams before certification. For endocrinologists and urologists who have already completed their formal training, the EAA and European Academy of Andrology will now also offer a level 1 Educational Program in Andrology, with a focus on male infertility and contraception, male sexual dysfunction, male accessory gland infections and STD counseling, and andrological endocrinology. The program and credit system are outlined.
Training in andrology: the level 1 programme of the European Academy of Andrology (EAA) and of the European Society for Andrological Urology ( ESAU).
Dohle GR, Giwercman A, Lenzi A, Weidner W, Forti G, Mirone V.
Int J Androl. 2007 Feb;30(1):1-2. No abstract available.
PMID: 17313539

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First Male Contraception Quarterly report released

The International Male Contraception Coalition has released the first issue of a quarterly report for policymakers, summarizing the quarter’s most intriguing clinical findings and best policy guidance. The report also presents the first analysis of market survey data collected since September of 2006, showing that men and women around the world are ready for new male contraceptives.

The centerpiece of the report is a list of the men and women who have identified themselves as potential customers of new male contraceptive products. Their signatures and personal letters – which explain why they care about this issue – fill six pages. Seven hundred and thirty-four people participated in the survey in its first quarter, and 584 men and women signed the letter to policymakers.

The quarterly reports will be ongoing, and the IMCC will keep a running tally of survey participants and signatories. As the numbers grow, so does the case for increased support for the work of male contraceptive developers.

This report should be an essential part of every researcher’s and policymaker’s arsenal when arguing for increased or sustained funding. In this era of budget cuts in science and reproductive health, a tool like this is vital to be able to quickly and eloquently respond to the inevitable question, “Do men really want this?”

The Quarterly is under a Creative Commons Attribution license, so it can be freely reproduced and excerpted provided it is attributed to the IMCC.

Read the report:
Male Contraception Quarterly, Number 1

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RISUG Phase III trial moves forward

RISUG, the vas-based injectable contraceptive polymer with efficacy of ten years or more, is moving forward again. Manufacturing difficulties have been resolved, and the Phase III trial is scheduled to be restarted this month. (The study on 140 men begun in 2001/2002 is now being called a “preliminary” Phase III trial, and this new cohort will be in the “extended” Phase III trial.)

The Indian Council for Medical Research worked with India’s Central Glass and Ceramic Research Institute to produce a glass syringe designed specifically for RISUG. The syringes have been manufactured for the trial, and the private company Marksans Pharma has manufactured RISUG and gotten the special syringes filled. Once the syringes are sterile packaged, the study centers can begin doing insertions.

The “extended” study design includes 10 centers throughout India with 50 men at each center. The first 4 of the centers have their paperwork done or nearly done and will start this month, and the remaining 6 will be a second round. The research team estimates that the recruitment phase will take about 2 years. They plan 3 to 5 years of follow-up after administering RISUG, so the total study duration will be up to 7 years.

Many men from Western countries write to MCIP asking how they can participate in a RISUG clinical trial, offering to fly to India at their own expense. However, this study in India is limited to men who live near the test centers, because regulatory agencies require standardized follow-up visits overseen by the same doctor. We hope 2007 will see collaborations between Indian and North American researchers to begin the process of preclinical studies in the U.S. or Canada, so that within this decade those men will be able to participate in a clinical trial closer to home.

We don’t have details yet on whether Marksans followed WHO Good Manufacturing Practice (GMP) standards or the more strictly-enforced International Conference on Harmonization (ICH) GMP standards while manufacturing RISUG. If ICH GMP standards were followed when making the material for the trial, it will shorten any FDA or ICH approval process by several years and save several million dollars, making eventual introduction outside India more likely. Check back next month for an update.

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Special contribution: Report from the 2007 No-Scalpel Vasectomy Surgeons of India Meeting

Vasectomy researchers and practitioners from around the world attended the meeting, including Prof. SK Guha and Prof. RCM Kaza of India; Prof. Michel Labrecque and Dr. Ron Weiss of Canada; and Dr. Doug Stein and Dr. David Sokal, USA. Research findings were reported on various techniques under development, including an update by Prof. Guha on RISUG, and by Dr. Doug Stein, USA, on the Shepherd Medical Intra-Vas Device (IVD). There were presentations and discussions on the use of cautery as a potential way to improve vasectomy effectiveness in India, and Mr. Ajay Saxena of Instrumed International, India, showed prototypes of a thermal cautery device manufactured in India.

As part of the meeting, Dr. Baljit Kaur, NSV-SI Vice Chair, arranged for an evening of lectures and discussion on the problem of “Missing Girls” in India. This refers to the low number of female babies being born compared to male babies due to selective abortion following ultrasound sex determination, a problem which is especially severe in and around Amritsar, the site of the meeting.

Thanks to Dr. David Sokal of Family Health International for contributing this summary.

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Funding opportunity: US-India collaboration on contraceptive development

A reissue of NICHD’s R03 grant for the Indo-US Program on Contraceptive and Reproductive Health Research (CRHR):

“The goal of the CRHR program is to support collaborative research that will result in expanded contraceptive options and improved reproductive health in the U.S., India, and globally, with specific emphasis on the need for more "translational" types of research intended to move beyond basic science and discovery to product development and delivery. Projects should be designed to achieve enhanced reproductive health, disease prevention, product development, and/or technology transfer. High priority areas include long-acting and hormonal contraceptives, identification and development of potential microbicides, and projects focused on biomedical and social-behavioral factors that influence reproductive health, effective family planning including strategies to address infertility in men and women, and disease prevention.”

For more information:
Read the grant announcement
Contact the Scientific/Research coordinator, Dr. Dan Raiten

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WHO summarizes findings on acceptability of a male hormonal contraceptive regimen

The World Health Organization has summarized the acceptability findings of two groups of their collaborating researchers in China and Italy, who tested injectable male hormonal contraceptives in their respective local cohorts. “Men participating in clinical trials of potential hormonal injectable contraceptives were interviewed over the course of the studies for their perspectives. Men in both trials found the experimental injectables to be generally acceptable, despite some shortcomings.”

From these findings, they conclude:

• “An injectable method of male fertility regulation has potential in China and Italy
• Further work to improve the features of the injectable is needed to enhance acceptability
• Users perspectives provide important insights for method development and refinement”

The poster is available for download.

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Contraceptive Technology attendees learn about your work

The 600 attendees of this year’s San Francisco Contraceptive Technology conference learned about emerging male contraceptives in the main session. Sharon Schnare, MSN, FNP, CNM, FAANP, presented “Future Contraception: What’s in the pipeline?” Ms. Schnare devoted half of her presentation to the latest information about the status of RISUG, male hormonal contraception, the Intra Vas Device, and Adjudin research. She will deliver the same presentation to an equal number of attendees at the Washington, DC, Contraceptive Technology conference at the end of the month. The nurses, PAs, CNMs and MDs we spoke to at the conference were excited to learn how many male contraceptive products are in advanced clinical trials, and excited to have other options for the men with whom they work.

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Press highlights: The Herald and the Lancet

Male hormonal contraception: “AKZO Nobel, the Dutch chemicals group, yesterday said the flotation of its Organon BioSciences drugs business was imminent, putting an end to rumours that the division would be snapped up by venture capitalists.”
Organon flotation ‘imminent’ says Akzo
The Herald, 16 February

“A new law that gives the director of US National Institutes of Health (NIH) greater control over the agency's budget could hurt already cash-strapped research programmes, say some patient advocacy groups and researchers. The reform, which President George W. Bush signed into law last month, gives NIH director Elias Zerhouni control over a common fund that he can use to support cross-cutting research initiatives that require the expertise of more than one NIH institute or centre.”
US NIH chief gains greater power over budget (Login required)
The Lancet, 24 February

“On December 13, 2006, the National Institutes of Health (NIH) announced the early termination of two randomised controlled trials of male circumcision—in Kenya and Uganda—on the basis of interim evidence that male circumcision provided a protective benefit against HIV infection of 53% among the 2784 Kenyan men and 51% among the 4996 Ugandan men enrolled in the respective studies.”
Male circumcision and HIV/AIDS: challenges and opportunities (Login required)
The Lancet, 24 February

There has been an interesting ongoing discussion of the implications of the male circumcision trial findings on Androlog. If you are not an Androlog subscriber, you can read the “Risk/benefit analysis of circumcision and HIV” thread in the Androlog archives.

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Calendar of events

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.

March 8-11	2nd World Congress on Gender-specific medicine and aging: the endocrine impact; Rome, Italy
March 15	Deadline for Mediterranean Society for Reproductive Medicine abstract submission
March 21-24	22nd Annual European Association of Urology Meeting; Berlin, Germany
March 28-31	Contraceptive Technology 2007 East Coast conference; Washington, DC, USA
April 15-19	1st World Congress for Sexual Health; Sydney, Australia
April 18-21	North American Testis Workshop; Tampa, FL, USA
April 20-23	6th Annual Congress of the Mediterranean Society for Reproductive Medicine “Recent Advances & Controversies”; Antalya, Turkey
April 21-24	American Society of Andrology 32nd Annual Conference; Tampa, FL, USA
April 25-27	20a Reunión de la Asociación Latinoamericana de Investigadores en Reprodución Humana; Buenos Aires, Argentina
April 28 - May 2	9th European Congress of Endocrinology; Budapest, Hungary
April 30 - May 5	IFFS 19th World Congress on Fertility and Sterility; Durban, South Africa
May 6 - June 17	Frontiers in Reproduction lab and lecture course for research careers in reproductive biology; Woods Hole, MA, USA
May 29 - June 28	East-West Center’s 38th Summer Seminar on Population “Communicating with Policymakers about Population and Health” Workshop; Honolulu, HI, USA
June 2-5	89th Annual Meeting of The Endocrine Society, ENDO 07; Toronto, Canada
July 1-6	Gordon Research Conferences Cell-Cell Fusion; New London, NH, USA
July 15-20	Gordon Research Conferences Fertilization and Activation of Development; Plymouth, NH, USA
September 27-28	2nd Future of Male Contraception conference; Seattle, WA, USA
November 3-7	American Public Health Association 2007 Annual Meeting “Politics, Policy & Public Health”; Washington, DC, USA

 

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Editors

Kirsten Thompson, Director of the Male Contraception 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