MALE CONTRACEPTION UPDATE

Summaries of new peer-reviewed publications

Retinoic acid receptor approach
“These results together suggest that retinoic acid receptor A protein (RARA) may function in Sertoli cells to promote the survival and development of early meiotic prophase spermatocytes, whereas RARA in germ cells functions to increase the proliferation and differentiation of spermatogonia, prior to meiotic prophase.”
Potential Functions of Retinoic Acid Receptor A (RARA) in Sertoli Cells and Germ Cells During Spermatogenesis.
Doyle TJ, Braun KW, McLean DJ, Wright RW, Griswold MD, Kim KH.
Ann N Y Acad Sci. 2007 Sep 28; [Epub ahead of print]
PMID: 17905941

Binding / Fusion targets
“We disrupted Zpbp1 and Zpbp2 in mice. Males lacking ZPBP1 were sterile, with abnormal round-headed sperm morphology and no forward sperm motility. Ultrastructural studies demonstrated that absence of ZPBP1 prevents proper acrosome compaction, resulting in acrosome fragmentation and disruption of the Sertoli-spermatid junctions. Males null for ZPBP2 were subfertile, demonstrated aberrant acrosomal membrane invaginations, and produced dysmorphic sperm with reduced ability to penetrate zona pellucida.”
Loss of zona pellucida binding proteins in the acrosomal matrix disrupts acrosome biogenesis and sperm morphogenesis.
Lin YN, Roy A, Yan W, Burns KH, Matzuk MM.
Mol Cell Biol. 2007 Oct;27(19):6794-805. Epub 2007 Jul 30.
PMID: 17664285 

Cell adhesion targets
“The coxsackievirus and adenovirus receptor (CAR) is a cell adhesion molecule expressed in epithelial tight junctions and other cell-cell contacts… CAR is not a general component of tight junctions in the seminiferous epithelium, and Sertoli cells in the adult testis do not express CAR. Instead, CAR expression is stage dependent and specifically found in migratory germ cells… Finally, an intermediate compartment occupied by CAR-positive, migrating germ cells and flanked by two occludin-containing junctions is identified.”
Coxsackievirus and Adenovirus Receptor Is Up-Regulated in Migratory Germ Cells during Passage of the Blood-Testis Barrier.
Mirza M, Petersen C, Nordqvist K, Sollerbrant K.
Endocrinology. 2007 Nov;148(11):5459-69. Epub 2007 Aug 9.
PMID: 17690169 

“The transcription factor Ets-variant gene 5 (ETV5) is essential for spermatogonial stem cell (SSC) self-renewal, as targeted deletion of the Etv5 gene in mice (Etv5(-/-)) results in only the first wave of spermatogenesis… While the role of these specific proteins upon the blood-testes barrier have not been investigated to date, related proteins and family members of those listed have been shown to be critical in modulating various components that contribute to blood-testes barrier function.”
ETV5 is required for continuous spermatogenesis in adult mice and may mediate blood-testes barrier function and testicular immune privilege.
Morrow C, Hostetler C, Griswold M, Hofmann MC, Murphy K, Cooke PS, Hess RA.
Ann N Y Acad Sci. 2007 Oct 2; [Epub ahead of print]
PMID: 17911411

Motility target supporting research
“Immunoblotting studies found that spermatogenic cell-specific type 1 hexokinase (HK1S) is abundant in sperm, and immunostaining confirmed that HK1S is located mainly in the principal piece of the sperm flagellum, where other spermatogenic cell-specific glycolytic enzymes have been found. These results strongly suggest that HK1, HK2, HK3, and GCK are unlikely to have a role in glycolysis in sperm and that HK1S encoded by Hk1_v2 and Hk1_v3 serves this role.”
Spermatogenic cell-specific type 1 hexokinase is the predominant hexokinase in sperm.
Nakamura N, Shibata H, O'brien DA, Mori C, Eddy EM.
Mol Reprod Dev. 2007 Oct 8; [Epub ahead of print]
PMID: 17924400

“Here we show that the accelerating action of HCO 3 - also requires the continued presence of external Ca 2+ (EC 50 approximately 0.5 mM)… Ca 2+ is required for HCO 3 - to elevate cAMP, but not for cAMP-AM to increase beat frequency, indicating that external Ca 2+ acts before rather than after stimulation of SACY by HCO 3 -… We propose that external Ca 2+ binds an unidentified extracellular protein that is required for HCO 3 - to engage cAMP-mediated activation of motility.”
External Ca 2+ acts upstream of adenylyl cyclase SACY in the bicarbonate signaled activation of sperm motility.
Carlson AE, Hille B, Babcock DF.
Dev Biol. 2007 Sep 20; [Epub ahead of print]
PMID: 17950270

Endocrinological approach supporting research
“We generated a [Leydig cell]-specific knockout mouse (L-AR(-/y)) with the androgen receptor gene deleted… L-AR(-/y) mice were infertile, with spermatogenic arrest predominately at the round spermatid stage and no sperm could be detected in the epididymis. L-AR(-/y) mice also have lower serum testosterone concentrations and higher serum leuteinizing hormone and follicle-stimulating hormone concentrations than AR(+/y) mice.”
Infertility with defective spermatogenesis and steroidogenesis in male mice lacking androgen receptor in Leydig cells.
Xu Q, Lin HY, Yeh SD, Yu IC, Wang RS, Chen YT, Zhang C, Altuwaijri S, Chen LM, Chuang KH, Chiang HS, Yeh S, Chang C.
Endocrine. 2007 Oct 23; [Epub ahead of print]
PMID: 17955388

“These results demonstrated that the decreased expression of ARA54 and increased expression of ARA55 is a feature of nonobstructive azoospermia. In addition, the differential localization of ARA54 may play an important role in testicular development and spermatogenesis in humans.”
Expression of androgen receptor co-regulators in the testes of men with azoospermia.
Lan KC, Hseh CY, Lu SY, Chang SY, Shyr CR, Chen YT, Kang HY, Huang KE.
Fertil Steril. 2007 Oct 3; [Epub ahead of print]
PMID: 17919607

Proteomic / genomic supporting research
“This review discusses microarray technology, proteomics, metabolic profiling, the PolScope, atomic force microscopy and microfluidics,” and their application to understanding the molecular basis of human fertility and infertility.
Emerging technologies for the molecular study of infertility, and potential clinical applications.
Varghese AC, Goldberg E, Bhattacharyya AK, Agarwal A.
Reprod Biomed Online. 2007 Oct;15(4):451-6.
PMID: 17908410

“Our results indicate, for the first time, that α1b-adrenergic receptor (AR) signaling plays a critical role in the control of male fertility, spermatogenesis, and steroidogenic capacity of Leydig cells. It is thus hypothesized that the absence of α1b-AR alters either directly germ cells or indirectly Sertoli cell/Leydig cell communications in infertile α1b-AR-KO mice.”
Fertility and spermatogenesis are altered in {alpha}1b-adrenergic receptor knockout male mice.
Mhaouty-Kodja S, Lozach A, Habert R, Tanneux M, Guigon C, Brailly-Tabard S, Maltier JP, Legrand-Maltier C.
J Endocrinol. 2007 Nov;195(2):281-92.
PMID: 17951539

Testicular angiotensin-converting enzyme (tACE) transgenic mouse lines with a dipeptidase-inactivated mutant tACE gene showed impaired sperm-zona pellucida binding. “The dipeptidase activity was reduced in epididymal ingredients but not in the testis. Furthermore, direct application of mutant protein did not suppress sperm-ZP binding of intact sperm during IVF, implying that the dipeptidase-inactivated mutant affects sperm modification in the epididymis for ZP binding.”
Dipeptidase-Inactivated tACE Action In Vivo: Selective Inhibition of Sperm-Zona Pellucida Binding in the Mouse.
Deguchi E, Tani T, Watanabe H, Yamada S, Kondoh G.
Biol Reprod. 2007 Nov;77(5):794-802. Epub 2007 Jul 18.
PMID: 17634445

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"Future of Male Contraception" abstracts online

You can now find all the presentation abstracts and poster abstracts from last month’s NICHD, NIH, and CONRAD “Future of Male Contraception” conference as a PDF at the conference website. Many thanks to Diana Blithe of NICHD for this update! The front page of the website also lists contact info for federal academic drug development resource programs; all investigators are encouraged to explore whether their work is eligible for these programs.

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Request for applications: NIH Specialized Cooperative Centers Program in Reproduction re-competition

“The National Institute of Child Health and Human Development (NICHD) provides funding for a limited number of research centers in the reproductive sciences. These centers provide an arena for multidisciplinary interactions among basic and clinical scientists interested in establishing high quality programs in reproduction and infertility research. The centers will also serve as national resources for the training and career development of new scientists electing to pursue research in high priority areas of reproduction and infertility research. The purpose of this RFA is to announce the annual re-competition of the Specialized Cooperative Centers Program in Reproduction Research now called the Specialized Cooperative Centers Program in Reproduction and Infertility Research... The NICHD intends to commit approximately $6.0 million in total costs in FY 2009 to fund up to four new and/or competing continuation grants in response to this RFA.”

A letter of intent must be received by April 23, 2008.
Read the full request for details.
Contact Dr. Louis DePaolo for further information: (301) 435-6970, ld38p@nih.gov

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Contraceptive cost and access

A chart in the new issue of “Dialogues in Contraception” strikingly illustrates why we need new contraceptives. In the United States, every contraceptive on the chart costs at least $1000 for two years of use, when method cost, unintended pregnancy costs, and medical complication costs are added together. Tubal sterilization for women tops the list, at a whopping $11,000.

Components of costs associated with contraceptive method use versus no method use over 2 years.*

What method is the most affordable? Surprisingly, vasectomy is the winner at about $1000 for two years, due to the much lower cost of surgery than for female sterilization, the low rate of complications, and fewer unintended pregnancies than for short-term methods. But vasectomy is considered permanent, so it is not appropriate for the majority of younger men.

Wouldn’t condoms and the Pill be cheaper than vasectomy surgery? No, it turns out that they both add up to twice as much — condoms due to costs of unintended pregnancies, and pills due to unintended pregnancies plus medical complications.

As we work to develop new contraceptives, keeping all three of these factors in sight will be crucial. New methods must be affordable: public-sector pricing agreements must be rigorously designed to assure this. But the new methods must also be highly effective, as even an 8% typical-use failure rate (such as for the Pill) can nearly double the per-person total cost to reproductive age women. And they must be as free from medical complications as possible, since complications require office visits and increase discontinuation rates.

The importance of contraceptive discontinuation should not be discounted: about 50% of US Depo-Provera users will quit each year, for example, and 17% of those will be pregnant within 6 months. With new male methods, there is an opportunity to raise the bar for all these factors: cost, pregnancy rates, complications, and continuation.

Read more
Assessing Costs and Improving Access to Contraception
Andolsek KM, Burkman RT.
Dialogues in Contraception, Fall 2007

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Press: the blogosphere and Ms.

Last month’s conference coverage in major press outlets has continued to ripple around the globe via blogs (over 200 of them) and news services. MCIP is particularly proud that the story was picked up by Ms. Magazine’s online service. It was the overwhelming response to a short 1992 Ms. Magazine article on the subject — over 200 letters, back in the era of envelopes and stamps — that inspired the original expansion of the Male Contraception Information Project, making this article something of a homecoming.

More Birth Control Options for Men on the Way
Ms. Magazine, 5 October

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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.

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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