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. 

Endocrine approaches
“We demonstrate here that T gel, when combined with DMPA, effectively contributes to sperm suppression, and is well tolerated… The addition of a potent GnRH antagonist, acyline, does not significantly enhance the rapidity and effectiveness of sperm suppression…”
“Testosterone gel combined with depomedroxyprogesterone acetate is an effective male hormonal contraceptive regimen and is not enhanced by the addition of a GnRH antagonist.” Page ST, Amory JK , Anawalt BD, Irwig MS, Brockenbrough AT, Matsumoto AM, Bremner W.
J Clin Endocrinol Metab. 2006 Aug 29; [Epub ahead of print]
PMID: 16940442

Men given T and DMPA with FSH or hCG (as an LH substitute) showed “all germ cell subtypes were maintained at control levels by either FSH or LH activity, except pachytene spermatocytes, which were found to be lower in the hCG vs. FSH and control groups… Future contraceptive treatment strategies must consider independent regulation of spermatogenesis by both FSH and LH / intratesticular androgens for maximum efficacy.”
“The relative roles of FSH and LH in maintaining spermatogonial maturation and spermiation in normal men.”
Matthiesson KL, McLachlan RI, O'donnell L, Frydenberg M, Robertson DM, Stanton PG, Meachem SJ.
J Clin Endocrinol Metab. 2006 Aug 8; [Epub ahead of print]
PMID: 16895950 

Men treated with acyline or acyline plus transdermal testosterone gel for 28 days showed “no detectable differences in prostate epithelial proliferation, apoptosis, PSA [or] androgen receptor expression” as compared to the control group.
“Persistent intraprostatic androgen concentrations after medical castration in healthy men.”
Page ST, Lin DW, Mostaghel EA, Hess DL, True LD, Amory JK, Nelson PS, Matsumoto AM, Bremner WJ.
J Clin Endocrinol Metab. 2006 Aug 1; [Epub ahead of print]
PMID: 16882745

There were no significant differences in serum concentrations of testosterone, bioavailable T, DHT, SHBG, or DHEAS between the tested ethnic groups.
“Serum androgen levels in Black, Hispanic and White men.”
Litman HJ, Bhasin S, Link CL, Araujo AB, McKinlay JB.
J Clin Endocrinol Metab. 2006 Aug 15; [Epub ahead of print]
PMID: 16912139

Age, however, has a significant impact on apparent testosterone metabolic clearance rates when exogenous T is given. Older men given monthly GnRH agonist and weekly TE injections for 5 months “had lower total and free testosterone, and higher SHBG than younger men at baseline,” all at P < 0.00001.
“Differences in the Apparent Metabolic Clearance Rate of Testosterone in Young and Older Men with Gonadotropin Suppression Receiving Graded Doses of Testosterone.”
Coviello AD, Lakshman K, Mazer NA, Bhasin S.
J Clin Endocrinol Metab. 2006 Aug 15; [Epub ahead of print]
PMID: 16912120

“These data provide direct evidence that production of activin A and inhibin B by the Sertoli cell is locally modulated by IL-1 α, in addition to FSH/cAMP, under the influence of the developing spermatogenic cells.”
“Regulated production of activin A and inhibin B throughout the cycle of the seminiferous epithelium in the rat.”
Okuma Y, O'Connor AE, Hayashi T, Loveland KL, de Kretser DM, Hedger MP.
J Endocrinol. 2006 Aug; 190(2):331-40.
PMID: 16899566

Report on “the ability of kisspeptin-10 to potently elicit GnRH release ex vivo and LH secretion in vivo at early stages (neonatal to juvenile) of rat postnatal development… In addition, we provide further functional evidence for the ability of kisspeptin to stimulate the hypothalamic release of GnRH; a phenomenon that requires the activation of phospholipase-C, mobilization of intracellular Ca2+ and recruitment of ERK1/2 and p38 kinases.”
“Ontogeny and mechanisms of action for the stimulatory effect of kisspeptin on gonadotropin-releasing hormone system of the rat.”
Castellano JM, Navarro VM, Fernandez-Fernandez R, Castano JP, Malagon MM, Aguilar E, Dieguez C, Magni P, Pinilla L, Tena-Sempere M.
Mol Cell Endocrinol. 2006 Aug 21; [Epub ahead of print]
PMID: 16930819

Cell adhesion targets
Direct administration of TNFα – which is an in vivo secretory product of rat Sertoli and germ cells -- significantly and transiently disrupted the blood testis barrier. “It seems that one of the primary targets of TNFα at the BTB is the tight junction integral membrane proteins: occludin, claudin-11, and their adaptor ZO-1.” This group is now investigating whether TNFα has an effect on basement membrane collagen function.
“Tumor necrosis factor α reversibly disrupts the blood-testis barrier and impairs Sertoli-germ cell adhesion in the seminiferous epithelium of adult rat testes.”
Li MW, Xia W, Mruk DD, Wang CQ, Yan HH, Siu MK, Lui WY, Lee WM, Cheng CY.
J Endocrinol. 2006 Aug;190(2):313-29.
PMID: 16899565 

Epididymal targets
The 5 protease inhibitors found in distinct segments of the mouse epididymis “contribute to the regulation of sperm maturation by regulating the proteolytic processing of the sperm membrane during epididymal transit.”
“Novel epididymal protease inhibitors with Kazal or WAP family domain.”
Jalkanen J, Kotimaki M, Huhtaniemi I, Poutanen M.
Biochem Biophys Res Commun. 2006 Aug 14; [Epub ahead of print]
PMID: 16930550 

Heat-based approaches
Male mice exposed to 36˚C ambient temperature for 24 hours showed significant reduction in their ability to mate successfully. Animals exposed to the heat over 3 days (8+8+8 hours) showed slower and less overall decline in sperm counts than animals exposed in one day (24 hours uninterrupted). Sperm from treated mice subjected to swim-up selection were able to bind to the zona pellucida, but were less able to penetrate the ova. This study was designed to explore the possible effects of increasing ambient temperatures on livestock fertility.
“Effect of heat stress on the fertility of male mice in vivo and in vitro.”
Yaeram J, Setchell BP, Maddocks S.
Reprod Fertil Dev. 2006;18(6):647-53.
PMID: 16930511 

Supporting research
Summarizes recent findings of the “discrepancy between human and murine sperm responses” in terms of their regulated volume decrease (RVD) mechanisms. “Differences in the RVD mechanisms between murine and human spermatozoa caution the use of a mouse model in search for clinical applications.”
“The Role of Potassium Chloride Cotransporters in Murine and Human Sperm Volume Regulation.”
Klein T, Cooper TG, Yeung CH.
Biol Reprod. 2006 Aug 30; [Epub ahead of print]
PMID: 16943364

The male germ cell specific Na,K-ATPase, the a4 isoform, is essential for sperm function. This study shows transcriptional regulation of the human Na,K-ATPase a4 gene, ATP1 A4, by cAMP and a testis-specific cAMP response element modulator (CREMt).
“The transcription factor CREMt and cAMP regulate promoter activity of the Na,K-ATPase a4 isoform.”
Rodova M, Nguyen AN, Blanco G.
Mol Reprod Dev. 2006 Aug 7;73(11):1435-1447 [Epub ahead of print]
PMID: 16894555

AEP1 is an acrosome-specific gene conserved across mammalian species, “expressed in the acrosomal cap of late-staged germ cells,” which “likely functions in acrosome-cap formation.” This group is now investigating the involvement of AEP1 in the “docking/tethering of vesicles to target membranes during acrosome formation.”
“Acrosome-specific gene AEP1: Identification, characterization and roles in spermatogenesis.” Luk JM, Lee NP, Shum CK, Lam BY, Siu AF, Che CM, Tam PC, Cheung AN, Yang ZM, Lin YN, Matzuk MM, Lee KF, Yeung WS.
J Cell Physiol. 2006 Aug 21; [Epub ahead of print]
PMID: 16924657

“Determination of androgen bioactivity in human serum samples using a recombinant cell based in vitro bioassay.”
Roy P, Franks S, Read M, Huhtaniemi IT.
J Steroid Biochem Mol Biol. 2006 Aug 5; [Epub ahead of print]
PMID: 16893644

Reviews
“Synopsis: 2006 Annual Meeting of the American Society of Andrology.”
Oates R, Bailey J, Brannigan R, Evans J, Prins G, Perreault Darney S, Viger R, Cuasnicu P, Bhasin S, Turner T, Huszar G, Wang C, Sigman M, Boekelheide K, Hellstrom W, Klinefelter G, Lamb D.
J Androl. 2006 Aug 9; [Epub ahead of print]
PMID: 16899815

“Minutes of the 14th European Workshop on Molecular & Cellular Endocrinology of the Testis.”
Gromoll J, Michel C, Kostova E, Tuttelmann F, Wistuba J, Yeung CH, Henke A, Stukenborg JB, Akinloye O, Nieschlag E.
Mol Cell Endocrinol. 2006 Jul 19; [Epub ahead of print]
PMID: 16859825

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Highlights from the Society for the Study of Reproduction Meeting

The Society for the Study of Reproduction held their 39th annual meeting in Omaha at the end of July. The meeting abstracts are now available online.

• Greg Fontenot and David Powell of Lexicon Genetic presented “Use of mouse knockout models for the study of spermatogenesis.” Of the >3,000 KO mice NIH and Lexicon have created and analyzed, “approximately 5%… exhibited male infertility… The protein products of these [disrupted] genes included kinases, enzymes, membrane bound proteins, GPCRs, proteases, transporters, phosphatases and secreted proteins… Male infertility resulted from a variety of reproductive defects, which included examples of testicular dysfunction, stage specific disruptions of spermatogenesis, abnormal spermiation, or motility defects (both pre and post-capacitation). The degree of sperm dysfunction varied. Projects were identified that demonstrated spermatogenic arrest at the level of either spermatogonia, primary spermatocytes, secondary spermatocytes, spermatids or elongating sperm. In many cases, the KO males were phenotypically normal…”
• Clémence Belleannee and colleagues from the Institut National de la Recherche Agronomique presented “Purification and identification of sperm surface proteins related to sperm maturation.” They identified surface proteins acquired during epididymal transit on boar, bull and ram sperm. “Between mature and immature spermatozoa, several different surface proteins have been electrophoretically characterized and most of them have been identified by mass spectrometry… The systematic identification of proteins on different species shows that important modifications occurred both on the surface membrane and in the inner membrane of spermatozoa during epididymal maturation. Among surface proteins which have been quantified and identified by mass spectrometry, numerous are non-abundant and low molecular weight surface proteins.”
• Fang Yuan and colleagues from the University of Louisville presented “Testicular phenotype in double LH receptor and FSH-b subunit knockout mice.” “To determine the testicular phenotype in the absence of both LH and FSH signaling, we generated double LHRKO/FSH-bKO knockout mice… Testosterone replacement therapy, which stimulated the resumption of spermatogenesis to mature sperm in LHRKO animals, was only capable of promoting the process to elongated spermatids in double knockouts… Simultaneous deprivation of LH and FSH signaling had a more dramatic effect on testicular phenotype than in LHRKO animals and testosterone replacement therapy that rescued fertility in LHRKO animals failed in double knockouts.”
• Edith Emond and colleagues from the Laval University presented “Evidence of differential expression of transcriptome and protein by the caput epididymal cells in the presence of mouse spermatozoa.” In an effort to learn how spermatozoa presence might regulate the function of the epididymal epithelium, “mice spermatozoa from cauda epididymis were co-incubated for 24 hours with immortalized epididymal cell line.” Newly manufactured proteins were isolated and identified. Their “results strongly suggest that spermatozoa can act as a paracrine factor on epididymal epithelial cells and induce gene expression and de novo protein synthesis and secretion.”
• Aleksandar Rajkovic and colleagues from Baylor College and MD Anderson presented “TOHLH1 is essential for spermatogonial differentiation.” They have identified a novel basic helix-loop-helix (bHLH) transcription factor expressed in the testis and ovary, Tohlh1. “In males, Tohlh1 is preferentially expressed in prespermatogonia and Type A spermatogonia. Loss of Tohlh1 causes infertility by disrupting spermatogonial differentiation into spermatocytes… Tohlh1 represents the first testis specific bHLH transcription factor that is essential for spermatogonial differentiation.”

Next month: Highlights from the Association of Reproductive Health Professionals Meeting and the Symposium on Spermatology.

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Male contraceptives in the popular press

The male contraceptive: hard to swallow
by Genevieve Roberts, The Independent, 22 August
“A lack of demand has held up the arrival of the male contraceptive. Until now.” A review of the status of hormonal male contraceptive research. Features an interview with Clint Witchalls, a man who participated in the Schering/Organon trial of depot testosterone undecanoate with etonogestrel implants. Mr. Witchalls is writing a book about the experience, which will be published in 2007 by Rowohlt.

Worm Sperm Points to Fertility Deficits
by Staff writer, Howard Hughes Medical Institute, 30 August
A study of the proteins responsible for sperm chromatin assemblage in worms “provides important targets for the study of infertility and contraception in humans.” The study’s PI, Barbara Meyer at the University of California Berkeley, explained the importance of this work, saying: “What is severely lacking in the study of contraception is the development of methods that could work in males.”

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Public support growing: 900 advocates now read newsletter

The Male Contraceptive Coalition is building a base of support for your work. Hundreds of advocates now receive its public newsletter, which provides lively coverage of press stories, research, and clinical trial developments. The newsletter has been essential in alerting men to the upcoming IVD clinical trial, and the strong public interest has convinced the IVD developers to expand their study to additional sites.

Meanwhile, the Male Contraception Information Project is working to ensure accurate coverage of this complicated topic in the press. MCIP was interviewed for an article which introduced the millions of Playboy readers to male contraceptive research. MCIP has also assisted with sources and fact-checking on articles appearing everywhere from Fox News to the Canadian Broadcasting Corporation.

Curious what the public is learning about your work? Public newsletters (along with back issues of this newsletter) are archived online.

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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!

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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