MALE CONTRACEPTION UPDATE

Summaries of new peer-reviewed publications

Motility targets
The calcium ion channels coded by the Catsper1 and CatSper2 genes have already been identified as essential for sperm hyperactivation and fertility. “Huayu Qi et al. have identified two other related proteins, CatSper3 and CatSper4, that are involved in [the hyperactivation] process. Although these two family members show relatively low homology to CatSper1, they too are expressed only in spermatozoa and are functional in the tail portion. Targeted disruption of the genes for either CatSper3 or CatSper4 in mice produced the same phenotype as for CatSper1 and CatSper2: loss of voltage-sensitive Ca²⁺-selective current, abrogation of sperm hyperactivity, and subsequent male infertility.”
All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility.
Qi H, Moran MM, Navarro B, Chong JA, Krapivinsky G, Krapivinsky L, Kirichok Y, Ramsey IS, Quill TA, Clapham DE.
Proc Natl Acad Sci USA. 2007 Jan 23; 104(4):1219-23. Epub 2007 Jan 16.
PMID: 17227845

“Analysis of the phenotype of mice that carry targeted disruptions of key components has provided much insight into the major signaling pathways of sperm. A daunting challenge that remains will be to learn how the shifting roles of cAMP, Ca²⁺, and pH, the ruling triumvirate of mediators, are coordinated to control the major alterations in flagellar functions and swimming behavior that occur during capacitation. It is likely that the rate-limiting step in meeting this challenge will be development of a new generation of tools for multiparametric monitoring of sperm functions and signaling processes.”
Wrath of the wraiths of CatSper3 and CatSper4.
Babcock DF.
Proc Natl Acad Sci USA. 2007 Jan 23;104(4):1107-8. Epub 2007 Jan 16.
PMID: 17227862

“Mouse Tekt4 [which shares 77.1% of its identity with its nearest human homologue] is a germ cell-enriched gene, most abundantly expressed in haploid round spermatids in the testis, and the protein is localized to the sperm flagella… Tekt4-null sperm exhibit drastically reduced forward progressive velocity and uncoordinated waveform propagation along the flagellum… [with their] ineffective flagellar strokes lead[ing] to approximately 10-fold higher consumption of intracellular ATP…”
Absence of tektin 4 causes asthenozoospermia and subfertility in male mice.
Roy A, Lin YN, Agno JE, Demayo FJ, Matzuk MM.
FASEB J. 2007 Jan 23; [Epub ahead of print]
PMID: 17244819

A description of the use of genome searching and planar bilayer reconstitution to identify K⁺-selective cGMP-gated channels in sea urchin sperm flagella. “The Sp-tetraKCNG channel, the first of its class, is evolutionarily located between K⁺-selective and voltage-dependent EAG (ether-a-go-go) channels, and the voltage-independent cationic CNG (cyclic nucleotide-gated) channels, both families possessing a CNBD (cyclic nucleotide-binding domain).”
Sp-tetraKCNG: A novel cyclic nucleotide gated K(+) channel.
Galindo BE, de la Vega-Beltran JL, Labarca P, Vacquier VD, Darszon A.
Biochem Biophys Res Commun. 2007 Jan 17; [Epub ahead of print]
PMID: 17254550

Indenopyridines
“The results of this study indicated that l-CDB-4022 consistently induced severe, but reversible oligospermia (less than 1 x 10 6 sperm/ejaculate as compared to 23.58 x 10 6 sperm/ejaculate prior to treatment) when administered orally as 7 daily doses to adult cynomolgus monkeys, a representative higher primate. The onset of oligospermia… occurred within 2 weeks of initiating treatment and lasted approximately 6 weeks, with complete recovery occurring in all males by 16 weeks… The changes in serum inhibin B levels in l-CDB-4022-treated monkeys suggest that l-CDB-4022 acts, at least in part, by affecting Sertoli cell function…”
Development of l-CDB-4022 as a Nonsteroidal Male Oral Contraceptive: Induction and Recovery from Severe Oligospermia in the Adult Male Cynomolgus Monkey (Macaca fascicularis).
Hild SA, Marshall GR, Attardi BJ, Hess RA, Schlatt S, Simorangkir DR, Ramaswamy S, Koduri S, Reel JR, Plant TM.
Endocrinology. 2007 Jan 11; [Epub ahead of print]
PMID: 17218411

Glycolipid metabolism targets
“Sphingomyelin synthase 2 (SMS2) is an enzyme that catalyzes the conversion of phosphatidylcholine and ceramide to sphingomyelin and diacylglycerol, and it is crucial to cellular lipid metabolism… The expression of SMS2 was limited to late round spermatids and elongating spermatids… in the acrosome region… SMS2 may play a crucial role in the lipid metabolism in acrosome formation and the plasma membrane restructuring from late round spermatids to early elongating spermatids.”
Cellular localization of sphingomyelin synthase 2 in the seminiferous epithelium of adult rat testes.
Lee NP, Mruk DD, Xia W, Cheng CY.
J Endocrinol. 2007 Jan; 192(1):17-32.
PMID: 17210739

“The effects of miglustat on spermatogenesis in mice are strain-dependent, while in rabbits the drug is ineffective. Evaluation of interstrain hybrid mice indicated that the sensitivity of spermatogenesis to miglustat is a quantitative trait. These studies pave the way for identifying the genetic factors underlying the strain/species differences in the effect of miglustat.”
The sensitivity of murine spermiogenesis to miglustat is a quantitative trait: a pharmacogenetic study.
Bone W, Walden CM, Fritsch M, Voigtmann U, Leifke E, Gottwald U, Boomkamp S, Platt FM, van der Spoel AC.
Reprod Biol Endocrinol. 2007 Jan 22; 5(1):1 [Epub ahead of print]
PMID: 17241468 

Endocrinological approaches
“The administration of exogenous testosterone [as subdermal crystalline T pellets] and etonogestrel [as Organon’s Implanon implants] resulted in similar mean testosterone concentrations to that in the control group.” There was no diurnal variation in serum testosterone levels in the treated men; Thus, “the diurnal variation in testosterone concentrations observed in the control group is probably due to a change in the secretion of testosterone by the testis rather than an alteration in the metabolic clearance rate…”
A diurnal variation in testicular hormone production is maintained following gonadotrophin suppression in normal men.
Walton MJ, Anderson RA, Kicman AT, Elton RA, Ossowska K, Baird DT.
Clin Endocrinol (Oxf). 2007 Jan; 66(1):123-9.
PMID: 17201811

“[T]his study demonstrates that the male hormonal contraceptive regimen of daily T-gel + DMPA injected every 3 months is acceptable to roughly one half of men, most of whom would use the method if it became commercially available. The T-gel is relatively easy for men to use and is less irritating to the skin than T patches, but some men perceive that the T-gel interferes with their daily activities…”
Acceptability of a combination testosterone gel and depomedroxyprogesterone acetate male contraceptive regimen.
Amory JK, Page ST, Anawalt BD, Matsumoto AM, Bremner WJ.
Contraception. January 17; [Epub ahead of print]
DOI 10.1016/j.contraception.2006.11.003

Supporting endocrinological research
A clinical report of a case which “highlights the unintentional transdermal absorption of testosterone sufficient to induce virilization in a couple who were aware of this potential problem.” A shared washcloth was the culprit.
Postmenopausal virilization after spousal use of topical androgens.
Merhi ZO, Santoro N
Fertil Steril. January 12; [Epub ahead of print]
DOI 10.1016/j.fertnstert.2006.07.1547

“The CYP17 deletion was found to have a profound effect on mitochondrial architecture… [T]he mitochondria of sperm from the chimeric mice were small, abnormally shaped and disorganized. Testosterone supplementation from birth to adulthood did not rescue abnormal sperm morphology, suggesting that in addition to its critical role in androgen formation, CYP17 is necessary for proper sperm development and function. These results suggest that the effects of the CYP17 deletion may be direct rather than through reduced androgen.”
Abnormal Morphology of Spermatozoa in Cytochrome P450 17{alpha}-hydroxylase/17, 20-lyase (CYP17) Deficient Mice.
Liu Y, Dettin L, Folmer J, Zirkin B, Papadopoulos V.
J Androl. 2007 Jan 24; [Epub ahead of print]
PMID: 17251596

“The transcripts affected by these Ar mutations encode a diverse array of proteins whose molecular functions support the contention that AR supports spermatogenesis in both a permissive and instructive fashion.”
Transcriptional Profiling of Androgen Receptor Mutants Suggests Instructive and Permissive Roles of AR Signaling in Germ Cell Development.
Eacker SM, Shima JE, Connolly CM, Sharma M, Holdcraft RW, Griswold MD, Braun RE.
Mol Endocrinol. 2007 Jan 23; [Epub ahead of print]
PMID: 17244764

A Call for evidence-based decision-making in the use of testosterone therapy for aging men. “The diagnosis of androgen deficiency in adult men is currently threatening to expand beyond the classical but numerically small horizon of pathological hypogonadism to encompass a broader range of conditions with a potentially huge number of new candidates for T treatment. This is a double-edged sword…” A response to the issuance of the Endocrine Society’s Clinical Practice Guideline Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes.
Commentary – Guideline for Male Testosterone Therapy: A European Perspective
Wu FCW.
J Clin Endo Metab. 2007 Feb; 92(2):418-9
DOI: 10.1210/jc.2006-2799

Immunological approaches
“The mRNA transcript of DQH protein was found in seminal vesicles and not in the testis, epididymis [or] prostate… Monoclonal antibodies reduced binding of sperm to oocytes and proved the role of DQH protein in the sperm-zona pellucida primary binding.”
Origin, localization and binding abilities of boar DQH sperm surface protein tested by specific monoclonal antibodies.
Maňásková P, Pěknicová J, Elzeinová F, Tichá M, Jonáková V.
Reprod Immunol. Jan 31; [Epub ahead of print]
DOI: 10.1016/j.jri.2006.11.003

Researchers cloned human sperm membrane protein 1 (hSMP1) and generated polyclonal antibodies against it. Immunofluorescence showed hSMP1 occurring on the acrosome of both human and mouse sperm, probably due to the “strong homology between hSMP-1 and mouse SPAG8.” In vitro experiments with mouse sperm showed the antibodies significantly reduced the acrosome reaction and zona pellucida binding in a concentration-dependent manner.
Inhibition of mouse acrosome reaction and sperm-zona pellucida binding by anti-human sperm membrane protein 1 antibody.
Cheng GY, Shi JL, Wang M, Hu YQ, Liu CM, Wang YF, Xu C.
Asian J Androl. 2007 Jan; 9(1):23-9.
PMID: 17187156

Supporting proteomic/genomic research
“A strong SPATA12 gene expression was observed in normal adult testis but was completely absent in fetal testis. Both in situ hybridization and immunohistochemical analysis showed that SPATA12 was expressed in seminiferous tubules of adult testis, more precisely in spermatocyte, spermatids and spermatozoa, [with] no expression in Sertoli… [or] Leydig cells… [T]he putative function of SPATA12 is to maintain the cell in a differentiated state and /or to suppress cell proliferation.”
Expression and possible functions of a novel gene SPATA12 in human testis.
Dan L, Lifang Y, Guangxiu L.
J Androl. 2007 Jan 24; [Epub ahead of print]
PMID: 17251597

“[T]he results of the present work indicate that testicular protein CRISP2, as previously reported for epididymal protein CRISP1, is both relevant for sperm-egg fusion and capable of interacting with complementary sites in the egg surface. The possible participation of these two CRISP proteins in sperm-egg fusion provides important information on the molecular mechanisms involved in this process and supports the idea of a functional cooperation between homologous molecules as a mechanism to ensure the success of fertilization.”
Evidence for the Involvement of Testicular Protein CRISP2 in Mouse Sperm-Egg Fusion.
Busso D, Goldweic NM, Hayashi M, Kasahara M, Cuasnicu PS.
Biol Reprod. 2007 Jan 3; [Epub ahead of print]
PMID: 17202389

“Like all stem cells, spermatogonial stem cells are characterized by two distinct responses to environmental cues: self-renewal or differentiation. An in depth analysis of the components of the spermatogonial stem cell niche will be necessary to understand these processes… Our study provides a first insight into the early response of spermatogonial stem cells to GDNF (glial cell line-derived neurotrophic factor) in vitro and identifies N-myc as a target of Ret signaling.”
Role of Src family kinases and N-Myc in spermatogonial stem cell proliferation.
Braydich-Stolle L, Kostereva N, Dym M, Hofmann MC.
Dev Biol. 2006 Dec 12; [Epub ahead of print]
PMID: 17222400

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2nd Future of Male Contraception conference announced for September

Mark your calendar: The National Institute of Child Health and Human Development (NICHD), the University of Washington and CONRAD have announced the second Future of Male Contraception conference. The conference will be held on September 27-28 in Seattle, Washington.

The conference will bring together investigators working in university, research center and pharmaceutical settings, as well as regulatory experts, sociologists and male reproductive health care specialists.

Topics to be covered include progress on new targets for male contraception (from spermatogenesis targets to activation and binding targets), clinical trials, hormonal male contraception, translational research from target identification to clinical application, hurdles to product development, and recommendations for future research.

The two day conference will feature short presentations on clinical research and an evening poster session. In order to maximize the meeting’s brainstorming and information-sharing potential, presenters are asked to describe their latest work but are not expected to prepare a formal publication.

The Male Contraception Coalition and Male Contraception Information Project will work to enhance press coverage of this year’s meeting. We look forward to seeing you there!

For further information about registration and attendance, see the conference website.

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Pharmaceutical companies shelve reproductive health research programs

In an editorial for an upcoming issue of Fertility and Sterility, Drs. Jerry Strauss and Gautam Chaudhuri chronicle the recent trend of pharmaceutical companies backing out of their reproductive health research programs. They cite Ortho-McNeil and Wyeth’s quiet discontinuation of their contraceptive R&D programs, and an uncertain future for Schering’s programs. “As a consequence of these changes, a generation of reproductive scientists with skills in product development will evaporate, and the expertise to train new scientists in this area will be gone…”

“What’s to be done? We will have to place our trust in the existing NIH-supported contraceptive development and infertility research centers, and committed individuals, including those recently released from companies that are eliminating their reproductive-health discovery programs, to keep on target. Even with the long time horizon, academic obstetrics and gynecology has got to get moving and produce researchers with expertise in this area. Small pharma and biotech need to step up to the plate. Moreover, what is likely to be the salvation of the field of family planning and fertility treatments should be considered: a concerted effort to outsource research and development and product development to countries such as Brazil, China, and India, which have contraceptive and reproductive health needs and emerging biotech and pharmaceutical industries.”

The impending intellectual gap predicted by Drs. Strauss and Chaudhuri could become an opportunity for academic and clinical andrologists to move their field forward. The emerging specialty of andrology has a number of advantages: it is exciting novel science, its researchers have access to a host of new biological methodologies and tools, and the community already has strong international ties. Let’s hope andrologists will capitalize on these advantages and build contraceptive research and development into its the core curricula, rising to the challenge of meeting the world’s growing demand for contraception. There are already more couples in need of birth control than ever before in human history!

The accelerated pace of pharma abandonment of research and development in family planning and fertility – will reproductive health technology be frozen in time?
Strauss JF 3rd, Chaudhuri G.
Fertil Steril. 2007 Jan 12; [Epub ahead of print]
PMID: 17224150

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Andrology milestone in Britain: Manchester gets a male reproductive health care clinic

The Manchester Royal Infirmary (MRI) has opened Britain’s first Centre for Andrology, which hopes to provide “a range [services for male] infertility, hormonal and sexual conditions.” The center will draw on the expertise of MRI “staff from reproductive medicine, andrology, urology and endocrinology.”

Dr. Fred Wu explained the impetus for creating the center: “Traditionally, women have accessed health care for female disorders through contraception and baby care services, but the equivalent male services don't exist - so their problems tend to be worse before they get help.” Dr. Wu hopes that providing services specifically for men will lead to faster diagnosis and treatment.

Centers like this one are an intriguing service provision model for emerging male contraceptive products. The residents of the Manchester area will undoubtedly benefit from the center’s elevated standards for male reproductive health care.

Read more:
First 'just for men' health centre opens
Manchester Evening News, 31 January

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How population growth affects the MDGs – Final report released

On January 31, the UK’s All Party Parliamentary Group on Population, Development and Health released the findings from 6 months of hearings on population issues. (See more analysis of the group’s preliminary findings, and how to use them as a resource, in the January MCU newsletter.) The group’s conclusion is that population growth will detrimentally affect nations’ ability to achieve seven out of the ten Millennium Development Goals (MDGs) set forth by the United Nations:

• MDG 1: Eradicate extreme poverty and hunger
  “The rapid pace of population growth in much of Africa and some other parts of the world means, despite global efforts, we are not even succeeding in keeping the numbers living in extreme poverty stable.”
• MDG 2: Achieve universal primary education
  “[I]n high population growth countries, the number of school age children can double every 20 years. Assuming class sizes of 40, an extra 2 million school teachers per year are required just to stand still.”
• MDG 3: Promote gender equality and empower women
  “Women with numerous pregnancies and life-long child care find it difficult to participate in education, markets or politics. Women without access to family planning are likely to be younger when they have their first child, and less able to space or limit subsequent births.”
• MDG 4: Reduce child mortality
  “The two most important causes of child mortality directly related to population growth are high fertility and reduced access to safe drinking water.”
• MDG 5: Improve maternal health
  “High fertility strongly increases a woman’s lifetime risk of dying from pregnancy related causes. One woman a minute dies from pregnancy, childbirth or unsafe abortion and 99% of these deaths occur in developing countries.”
• MDG 6: Combat HIV/AIDS, malaria and other diseases
  “Population growth has a negative impact on gaining control over the spread of HIV/AIDS through two main routes: increased urbanization and the persistence of poverty.”
• MDG 7: Ensure environmental sustainability
  “Reversing the loss of environmental resources cannot be achieved in the context of rapid or even moderate population growth.” Access to fresh water is of particular concern: “As population grows, the UN estimates two thirds of the world’s population will face moderate to high water shortages by 2025.”

“It is clear that without addressing the issue of population growth and high fertility in the poorest regions of the world, these regions have little chance of achieving the Millennium Development Goals (MDGs)… Birth rates have been shown to decline when the option of family planning is made easily available. Urgent action must be taken to ensure family planning provision becomes an integral part of all efforts to reduce poverty, improve mothers’ and children’s survival and health, and to forestall further damage to the natural environment. The large and well-documented unmet need for family planning must be addressed… Helping couples to achieve their fertility goals is a fundamental and internationally recognized human right and will at the same time help to ensure a safer, more peaceful and healthier environment for tomorrow’s children.”

Read more:
The Return of the Population Growth Factor - its impact on the millennium development goals
Report of Hearings by the All Party Parliamentary Group on Population, Development and Reproductive Health, January 2007

Population growth and the Millennium Development Goals
By Drs. Malcolm Potts and Jean-Christophe Fotso in the Lancet, 369(9559):354-5.

Birth rates 'must be curbed to win war on global poverty'
The Independent, 31 January

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Press highlights – NY Times, Nigerian Tribune, Playboy, Reuters, Cavalier Daily

Dr. David Clapham at Harvard Medical School explains how his lab came to study sperm ion channels.
A Conversation With David E. Clapham – Small Wonders: Understanding the Way of the Warrior Sperm (Login required)
The New York Times, 23 January

Perspectives of men in Ibadan, Esa Oke, and Iloko-Ijesha on using novel male contraceptive products.
Male contraceptive pill promises heaven on earth
The Nigerian Tribune, 31 January

The February issue of Playboy begins a series of in-depth reports on the science of male sexuality. The first in the series explains the functionality of “a sperm cell and its delicate payload, the underrated Y chromosome.” A sidebar features a summary of new male contraceptive leads.

A petition against the use of desogestrel in third generation hormonal contraceptives for women – citing increased blood clot risk – is delivered to the US Food and Drug Administration.
Some newer contraceptives too risky, US group says
Reuters, 6 February

A summary of Dr. John Herr ’s work as both the director of UVA’s Center for Research in Contraceptive and Reproductive Health and a founder of ContraVac, Inc.
University researchers work toward developing male contraceptive drug
The Cavalier Daily, 6 February

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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 5-9	Deadline for American Public Health Association abstract submission
February 8-10	No Scalpel Vasectomy Surgeons of India meeting “An International Workshop on No Scalpel Vasocclusion”; Amritsar, Punjab, India
February 19-21	Conference on Recent Advances and Challenges in Reproductive Health & Research, and the 17th Annual Meeting of the Indian Society for the Study of Reproduction and Fertility (ISSRF); New Delhi, India
February 20-25	Keystone Symposium “Reproduction: Advances and Challenges”; Santa Fe, NM, USA
March 5-8	Society for Endocrinology Annual BES Meeting; Birmingham, UK
March 7-10	Contraceptive Technology 2007 West Coast conference; San Francisco, CA, USA
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 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