MALE CONTRACEPTION UPDATE

Summaries of new peer-reviewed articles

Indazoles
A single oral dose of gamendazole caused 100% infertility in rats at both 6mg/kg and 3mg/kg doses. In the respective treatment groups, 4 of 7 and 4 of 6 animals returned to normal fertility within 9 weeks. “Our results demonstrate that additional dose finding studies are required to improve reversibility and widen the therapeutic window before more detailed drug development of this potential non hormonal male contraceptive agent can occur.”
A Novel Potent Indazole Carboxylic Acid Derivative Blocks Spermatogenesis and Its Contraceptive in Rats after a Single Oral Dose.
Tash JS, Attardi B, Hild SA, Chakrasali R, Jakkaraj SR, Georg GI.
Biol Reprod. 2008 Jan 23 [Epub ahead of print]
PMID: 18218612

A study identifying binding targets of Gamendazole. “These data suggested that gamendazole may represent a new class of selective HSP90AB1 and EEF1A1 inhibitors… AKT1, NFKB, and interleukin 1 are known regulators of the Sertoli cell spermatid junctional complexes... [This] pathway [may] link interaction with HSP90AB1 and EEF1A1 to the loss of spermatids and resulting infertility.”
Gamendazole, an Orally Active Indazole Carboxylic Acid Male Contraceptive Agent, Targets HSP90AB1 (HSP90BETA) and EEF1A1 (eEF1A), and Stimulates Il1a Transcription in Rat Sertoli Cells.
Tash JS, Chakrasali R, Jakkaraj SR, Hughes J, Smith SK, Hornbaker K, Heckert LL, Ozturk SB, Hadden MK, Kinzy TG, Blagg BS, Georg GI.
Biol Reprod. 2008 Jan 23 [Epub ahead of print]
PMID: 18218611

Indenopyridines
“[These] results suggest that l-CDB-4022 activates the MAPK pathway, reduces expression of prosurvival factors such as the membrane form of SCF, alters expression of Sertoli-germ cell adherens junction proteins, disrupts Sertoli cell microtubule structure, and induces the proapoptotic factor, Fas, culminating in germ cell loss from the seminiferous epithelium.”
Mechanism of Action of l-CDB-4022, a Potential Nonhormonal Male Contraceptive, in the Seminiferous Epithelium of the Rat Testis.
Koduri S, Hild SA, Pessaint L, Reel JR, Attardi BJ.
Endocrinology. 2008 Jan 3 [Epub ahead of print]
PMID: 18174280

RISUG
“RISUG^® being a highly charged molecule, as evident from zeta potential measurements, has a tendency to form a complex with ionic biomolecules present in the seminal plasma… This RISUG(R)-biomolecule complex possibly acts as an ionic trap for spermatozoa passing through the vas deferens.”
Study of the micro-structural properties of RISUG^® - A newly developed male contraceptive.
Kumar S, Roy S, Chaudhury K, Sen P, Guha SK.
J Biomed Mater Res B Appl Biomater. 2007 Dec 27 [Epub ahead of print]
PMID: 18161821

Review
For novel male contraceptives, a “wide margin is… required between the effective dose range and doses that cause toxicity. It might be preferable that a male contraceptive, in particular a non-hormone-based compound, is delivered specifically and/or directly to the testis and has a rapid metabolic clearance rate, reducing the length of exposure in the liver and kidney.” Novel delivery mechanisms are outlined: A “drug might also enter the seminiferous epithelium to exert its action by simple diffusion via the basolateral Sertoli cell plasma membrane. Equally important, the entry of a drug into Sertoli cells might also be regulated by drug transporters. Alternatively, a drug can be conjugated to a ‘carrier’, such as an FSH or a transferrin mutant protein.”
Delivering non-hormonal contraceptives to men: advances and obstacles.
Mruk DD, Cheng YC.
Trends Biotechnol. 2008 Jan 10 [Epub ahead of print]
PMID: 18191256

“The theme for the XIX North American Testis Workshop, ‘Chromosome Structure and Gene Expression’ recognized the explosion of new information made possible by the far-reaching advances in genomics. While the process of decoding linear genome sequences was rapid and is nearing completion, the process of defining the genetic programs, epigenetic influences, and signaling events that regulate gene expression at the chromosome and transcript levels has a long way to go… [The] articles that resulted from [the Workshop] are included in this volume.”
Overview: testicular chromosome structure and gene expression.
Eddy EM, Griswold MD.
Ann N Y Acad Sci. 2008 Jan;1120:xi-xv.
PMID: 18184908

Motility/capacitation targets
“Cholesterol efflux from the sperm surface and protein kinase A-dependentphosphorylation play major regulatory roles in capacitation but the link between these two phenomena is unknown. We report that apolipoprotein A-I binding protein (AI-BP) is phosphorylated downstream to PKA activation, localizes to both sperm head and tail domains, and is released from the sperm into the media during in vitro capacitation.” AI-BP could provide “a link between protein phosphorylation and cholesterol efflux.”
Biochemical and structural characterization of apolipoprotein A-I binding protein, a novel phosphoprotein with a potential role in sperm capacitation.
Jha KN, Shumilin IA, Digilio LC, Chertihin O, Zheng H, Schmitz G, Visconti PE, Flickinger CJ, Minor W, Herr JC.
Endocrinology. 2008 Jan 17 [Epub ahead of print]
PMID: 18202122

“Potassium voltage-gated channel Isk-related family member 1 (KCNE1) is probably the major K⁺-channel involved in regulatory volume decrease in human spermatozoa, and channel activity is regulated beyond the extent of protein expression.”
Potassium channels involved in human sperm volume regulation-quantitative studies at the protein and mRNA levels.
Yeung CH, Cooper TG.
Mol Reprod Dev. 2007 Dec 21 [Epub ahead of print]
PMID: 18157847

Blood-testis barrier elucidation
“We now report findings on a novel mechanism utilized by the testes to regulate… the "opening" of the BTB above a migrating preleptotene/leptotene spermatocyte and the "resealing" of the barrier underneath this cell… When T or TGF-beta2 was added to Sertoli cell cultures with established functional BTB, both factors accelerated the kinetics of internalization of BTB proteins [occludin, JAM-A, and N-cadherin] from the cell surface, perhaps above the migrating preleptotene spermatocyte, thereby opening the BTB. Likewise, T also enhanced the kinetics of recycling of internalized biotinylated proteins back to the cell surface, plausibly relocating these proteins beneath the migrating spermatocyte to reassemble the BTB. In contrast, TGF-beta2 targeted internalized biotinylated proteins to late endosomes for degradation, destabilizing the BTB.”
Blood-testis barrier dynamics are regulated by testosterone and cytokines via their differential effects on the kinetics of protein endocytosis and recycling in Sertoli cells.
Yan HH, Mruk DD, Lee WM, Cheng CY.
FASEB J. 2008 Jan 11 [Epub ahead of print]
PMID: 18192323

Heat-based approaches
A report of the heat flux (watts/m²) and scrotal skin temperature uder various environmental conditions.
Relationship between ambient temperature and heat flux in the scrotal skin.
Song GS, Seo JT.
Int J Androl. 2008 Jan 22 [Epub ahead of print]
PMID: 18217986

Endocrinological supporting research
“Knowledge of the genes affected [during gonadotropin withdrawal], in both the presence and absence of additional progestogen, will give insight into the regulation of human testicular function and aid development of novel contraceptive methods… Microarray analysis shows that inter-individual variability is markedly low and the response to treatment [of a GnRH antagonist plus T] is focused on a small subset of genes particularly related to pathways in steroidogenesis and cholesterol biosynthesis or metabolism, the Leydig cell gene INSL3, and genes involved in early meiosis or Sertoli-germ cell junctions… No major changes in gene expression were identified in men additionally treated with a progestogen…”
Molecular profiling of the human testis reveals stringent pathway-specific regulation of RNA expression following gonadotropin suppression and progestogen treatment.
Bayne RA, Forster T, Burgess ST, Craigon M, Walton MJ, Baird DT, Ghazal P, Anderson RA.
J Androl. 2007 Dec 26 [Epub ahead of print]
PMID: 18160741

Genomic / proteomic supporting research
“How these expression data, combined with additional bioinformatic data analysis and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analysis, led to the identification of 58 genes that have 1000-fold higher expression transcriptionally in the testis when compared to over 20 other nonreproductive tissues is described. The products of these genes may play important roles in testicular and/or sperm function, and further investigation on their utility as nonhormonal contraceptive targets is warranted… The microarray data and the qRT-PCR data described are available in the Mammalian Reproductive Genetics database.”
Identification of Testis-Specific Male Contraceptive Targets: Insights from Transcriptional Profiling of the Cycle of the Rat Seminiferous Epithelium and Purified Testicular Cells.
Johnston DS, Jelinsky SA, Zhi Y, Finger JN, Kopf GS, Wright WW.
Ann N Y Acad Sci. 2008 Jan;1120:36-46.
PMID: 18184910

“[Integration of] the proteome with the sperm metabolome [will allow us to] not only understand the cascade of post-translational modifications (e.g., phosphorylation, glycosylation, proteolytic cleavage) involved in generating a functional spermatozoon but also determine how these physiological changes are brought about. This fundamental information will then create a basis for identifying key points in the post-testicular maturation of spermatozoa that might be targeted for contraceptive purposes or implicated in the defective sperm function observed in a significant proportion of infertile males.”
The role of proteomics in understanding sperm cell biology.
Aitken RJ, Baker MA.
Int J Androl. 2007 Dec 30 [Epub ahead of print]
PMID: 18179557

“In this report, we describe the molecular cloning and characterization of a mouse spermatid-specific manchette-related protein 1 (Smrp1) from a spermatid-specific subtracted mouse testis cDNA library… The protein appeared in a cap formation that covered the caudal sides of the elongated nuclei. This localization pattern coincided with that of the manchette. SMRP1 may play an important role as a functional protein that co-operates with manchette proteins.”
Isolation and characterization of the spermatid-specific Smrp1 gene encoding a novel manchette protein.
Matsuoka Y, Miyagawa Y, Tokuhiro K, Kitamura K, Iguchi N, Maekawa M, Takahashi T, Tsujimura A, Matsumiya K, Okuyama A, Nishimune Y, Tanaka H.
Mol Reprod Dev. 2007 Dec 28 [Epub ahead of print]
PMID: 18163442

“Msj-1 gene encodes a DnaJ protein highly expressed in spermatids and spermatozoa of both rodents and amphibians, possibly involved in vesicle fusion and protein quality control by means of interaction with heat shock proteins.” The researchers have identified a putative human homolog of msj-1. “[Expression] analysis, conducted by RT-PCR in human sperm cells, demonstrated that Ha mRNA is effectively present in humans; by Western blot, a specific MSJ-1 band of approximately 30kDa was detected in human sperm.”
Structure of msj-1 gene in mice and humans: A possible role in the regulation of male reproduction.
Meccariello R, Berruti G, Chianese R, De Santis R, Di Cunto F, Scarpa D, Cobellis G, Zucchetti I, Pierantoni R, Altruda F, Fasano S.
Gen Comp Endocrinol. 2007 Dec 4 [Epub ahead of print]
PMID: 18184612

“Prostate relaxin is a main source of this peptide in the seminal plasma. The relaxin effects on sperm motility and fertilization have been reported. The expression of other relaxin related peptides, such as INSL5 and INSL6 was described in testis; yet, currently there are no experimental data to pinpoint their biological functions. The other member of relaxin peptide family, insulin-like 3 peptide (INSL3),” has been better characterized. “[In] this chapter we review the data related to the expression and function of relaxin and related peptides in male reproduction.”
Relaxin and related peptides in male reproduction.
Agoulnik AI.
Adv Exp Med Biol. 2007;612:49-64.
PMID: 18161481

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Funding opportunity: NICHD Male Contraceptive Development Program

Dr. Diana Blithe of the National Institute of Child Health and Human Development urges researchers to check out the following funding announcement:
Request for Applications for the Male Contraceptive Development Program (RFA-HD-08-005)

“The aim of the program is to support both basic and applied research, with the ultimate goal of developing clinically useful products to regulate male fertility. This RFA solicits novel approaches to male contraception including, but not limited to, research on epididymal function, spermatogenesis, sperm function, and regulation of germ cell apoptosis… This funding opportunity will use the National Institutes of Health (NIH) specialized cooperative research award (U01) mechanism.”

We at IMCC and MCIP hope to see some great proposals competing for the NICHD's $2 million in 2008.  Applicants may request up to $200,000 direct costs per year, for a period of up to 5 years. This RFA is perfect for anyone developing a male contraceptive who doesn't yet need millions.  Consider applying even if your research isn't the "hot" thing – let the grantmakers choose their priorities among all options.  We've been working for increased funding for years, so let's take advantage of it!

Upcoming deadlines
Letters of Intent Receipt Date: April 16, 2008
Application Receipt Date: May 16, 2008

For further information, contact Diana Blithe.

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It’s been another year: What is the status of research?

It’s 2008; how did the various male contraceptive methods being studied fare during 2007? Here's a quick summary, with a focus on the methods in clinical trials:

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2008 Research wish list

Male contraception research has made great strides in the past year, with overwhelming evidence of public demand, several new studies started, and the September "Future of Male Contraception" conference cementing the new energy and enthusiasm. Where would we like to be a year from now? Here's Elaine Lissner of MCIP’s wish list, what we'd like to be reporting to you at the end of 2008:

• Preclinical research on the 5 unexplored Tripterygium wilfordii extracts underway. Triptolide did not work out, but researchers could test the other five extracts: tripchlorolide, tripdiolide, triptolidenol, 16-hydroxytriplide, and T7/19. The parent compound, a readily-available Chinese herb, is used in the treatment of autoimmune diseases and is known to have contraceptive effect; the goal is an extract that has contraceptive but not immune action. A small clinical study could also be initiated to confirm the contraceptive effect (as reported in the Chinese Journal of Andrology) and examine the safety of glycosides of T. wilfordii, another readily-available preparation.
• Progression of Shepherd Medical Company’s Intra Vas Device clinical trials to Phase II.
• Initiation of RAR-A trials in a primate model.
• FDA guidance on the next step for testicular ultrasound — possibly a clinical trial with men planning vasectomy — upon successful results from the current study.
• Foundation funding allowing the first India-US collaboration on RISUG: large-scale GMP manufacturing followed by a rabbit study. In addition, release by the Indian Council for Medical Research of results of the long-term follow-up study (based on interviews and exams of the several hundred men who have had RISUG 5 to 7 years), providing the first published data on RISUG's long-term effects in humans.
• Planning underway for the next "Future of Male Contraception" conference. NICHD, USAID, WHO, and foundation collaboration to assure travel funds for developing country researchers and policymakers, particularly those conducting advanced-stage clinical trials in India and China.

Kirsten Thompson of the IMCC adds the following items:

• Preliminary guidance from the FDA regarding standards for male contraceptive approval.
• Coordinated research & development grantmaking underlain by a transparent and cohesive prioritization process.
• A survey of North American doctors and family planning providers to understand their attitudes toward novel male contraceptives, so that we may begin positioning new products as they become available.

These are just some of the advances we hope to be able to report at the end of 2008. They haven't happened yet, but you may play a part in making them happen! And when you have an exciting advance to pass along to your colleagues, let us know!

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Press coverage

Male contraception hits the humor column! "Unconfirmed Sources" presents a parody story on "Plan D," the supposed experimental male contraceptive mistakenly released by the manufacturer "Barred Pharmaceuticals."  Women who gave it to their partners reported "an overall diminished interest in sex from their partners with an increase in their emotional attention span" and "no real adverse side effects such as sedation, and in fact, their partners appear to be more energetic and involved with completing household chores." Of course the real male contraceptives in development aim to work without changing hormone levels, leaving men and women to divvy up household chores without pharmaceutical intervention...
Experimental Plan D Released as Over the Counter by Mistake [parody]
Unconfirmed Sources, 8 January

Humorous column, with comments, by an Australian bloke on how he talked himself into a vasectomy after hearing lots of myths and having one false start. "The operation was as smooth as a gravy sandwich. As the hot laser deftly did its work, I found myself humming Jerry Lee Lewis's immortal lines…"
Taming of the cue
The Sunday Times (Perth), 11 January

Dr. R.S. Sharma, Deputy Director General of the Indian Council of Medical Research, gives an update on the RISUG clinical trials process, mentioning that the current study has been extended to 10 centers in India.
Injectable male contraceptive trial enters phase III
Daily News and Analysis India, 25 January

Researchers in Australia are trying to design a radio-controlled vas device.
Radio-controlled sperm 'tap' turns off vasectomies
New Scientist, 28 January

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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.

February 1	Deadline for ESHRE meeting 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 2-7	Joint meeting of the 15th European Testis Workshop and the Nordic Association for Andrology; Naantali, Finland
May 3-7	10th European Congress of Endocrinology; Berlin, Germany
May 15	Deadline for ASRM meeting abstract submission
May 26-28	1st World Congress on Reproductive Biology; Kona, HI, USA
June 9-15	International Men’s Health week
July 6-9	European Society for Human Reproduction and Embryology 24th Annual Meeting; Barcelona, Spain
July 6-11	Gordon Research Conferences – Ion Channels; Tilton, NH, USA
August 3-8	Gordon Research Conferences – Reproductive Tract Biology; Andover, NH, USA
September 26	World Contraception Day
November 8-12	American Society for Reproductive Medicine 64th Annual Meeting; San Francisco, CA, USA

 

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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