The American Society of Andrology Annual meeting was held in Phoenix Arizona, March 29-April 1, 2003. While about 20% of the abstracts were submitted by our international colleagues, many were unable to attend the meeting due to the war in Iraq, and were sincerely missed.
This year the ASA also sponsored the North American Testis Workshop which preceded the annual meeting on March 26-29. Organized by Mary Ann Handel, Ph.D. and Matt Hardy, Ph.D., the Testis Workshop theme was “Functional Genomics of Male Reproduction,” and included a keynote address on “Insights from the testicular transcriptome” by Michael Griswold, Ph.D., and a benchmark lecture on “Functional analysis of germ cell-specific genes” by Martin Matzuk, Ph.D..
The ASA annual Postgraduate Course, organized by Arthur Burnett, M.D., was held on March 29, and featured eight talks on “Erectile Dysfunction and Androgens,” the proceedings of which will be published in the Journal of Andrology. The Andrology Laboratory Workshop, organized by Greg Kopf, Ph.D., Pasquale Patrizio, M.D., and Charles Muller, Ph.D., expanded upon the theme “Partnerships in the Andrology Laboratory: Integration of Clinical Andrology, Basic Science and the Pharmaceutical Industry.”
Victor D. Vacquier, Ph.D. (Scripps Institute of Oceanography, U. California) opened the ASA meeting with the Serono Lecture on the fascinating topic “The evolution of gamete recognition proteins.” These include sperm chemoattractants which have arisen independently many times in evolution, with brand new evidence for their existence in mammals (Science, April 2003). Dr. Vacquier explained how gamete recognition proteins evolve very fast by a process called “positive selection” and gave examples of proteins that show a high level of interspecies differences due to this rapid evolution including: TP2, ZP2, P15, acrosin, P2 and ZP3. Furthermore, the genes for these proteins typically vary at the site that is critical for their biological activity while the rest of the gene is conserved. Examples for this feature include the well-studied sperm genes for zona adhesion, fertilin alpha and beta, PH20, acrosin, SAM 1 and SP17. Rapid evolution is thought to be important to create barriers for cross-species fertilization as would be particularly important for marine species such as sea urchins and abalones which shed their gametes into the ocean in close proximity to those of other species.
Dr. Bosl spoke on "Germ cell cancer: etiology, detection and cure: 2003." He indicated that 90% of germ cell tumors originate in the testis and 5% in the mediastinum. These tumors are 30-50 times more common in Caucasians than in African-Americans and are curable in over 90% of patients. About 7500 new patients with germ cell tumors will be seen in this country during 2003. The incidence of these tumors is 9.9 per 100,000 men in the 15 to 34-year-old age group. The various types of germ cell tumors were reviewed and Dr. Bosl emphasized that there is no such thing as "pure teratoma" because such tumors have the potential for metastatic disease.
The 2003 AUA speaker was GeorgeJ. Bosl, M.D. from Memorial Sloan-Kettering Cancer Center in New York. Germ cell tumors generally are categorized either as seminoma or non-seminomatous germ cell tumors. Patients with seminoma are grouped into either "good" or "intermediate" risk categories and Dr. Bosl indicated that there is no "poor" risk category of seminoma patients. However, non-germ cell tumor patients may have either "good," "intermediate," or "poor" risk potential. Serum markers of germ cell tumors are alpha-fetoprotein (AFP), human chorionic gonadotrophin (HCG) and lactic dehydrogenase (LDH). Dr. Bosl gave a detailed discussion of the development of chemotherapy for treatment of germ cell tumors. The current therapy, which includes Bleomycin, Etoposide and cis-platin, achieves a 94% cure rate in good risk patients. Unresponsive or relapsed germ cell tumors still are curable in up to 70% of patients with new chemotherapeutic regimens. If there is no relapse of malignant disease within two years, most patients are cured. Dr. Bosl reviewed early and late toxicity of the various chemotherapeutic agents. He concluded by mentioning that i(12p) seems to be a pathogenic cytogenetic marker of germ cell tumors. He felt that such molecular markers may play a significant role in the diagnosis and perhaps treatment of germ cell tumors in the future.
In a lecture entitled “Regulation of Segmented Function in the Epididymis” Terry Turner, Ph.D. (U. Virginia) showed us the latest evidence from his lab group that specific genes, particularly those involved in segmentation of embryos, such as Hox and Sonic Hedgehog genes, are differentially expressed in the discrete segments of the epididymis where they may help account for segment-specific organ function. The use of gene expression arrays is helping his lab and others to better characterize patterns of gene expression in the epididymis and reveal embryonic genes that continue to play roles in adult function.
Barry Zirkin, Ph.D. (Johns Hopkins U. in Maryland) and Bernard Robaire, Ph.D. (McGill U. in Montreal, Canada) teamed up to provide insights on “Male Reproductive Aging: Mechanisms and Consequences.” They study Brown Norway rats, a strain that ages gracefully, without getting fat or developing tumors. Barry showed that Leydig cells (LC) from old rats produce less testosterone than those from young rats. Through a clever series of experiments in which LCs were reversibly suppressing for extended periods of time, he could keep LCs young in old testes! He concludes that LC age due to intrinsic factors, likely related to damage from reactive oxygen species. Bernard then showed novel evidence that sperm from old rats are also less healthy as evidenced by altered motion characteristics, increased susceptibility to oxidative stress, increased incidence of sperm aneuploidy and chromatin instability, and other markers of genomic integrity such as DNA methylation. Such changes have implications for reproductive success in older men.
A Memorial Symposium consisting of three talks honored Dr. Lonnie Russell, who died unexpected last summer, for his major contributions to the study of spermatogenesis. Rex Hess, Ph.D., from The University of Illinois titled his talk "Complexity of the Testis made Simple and Fun," and based it upon Lonnie’s unique talent to tackle complex subjects and to simplify the teaching of these topics, as illustrated in his book, "Molecular Biology made Simple and Fun." Given in a joyful and free-spirited manner to remind us of Lonnie’s fun-loving and insightful characteristics, this lecture spoke of the components of the testis, and how to evaluate spermatogenesis using a method to simplify the identification of Stages in the cycle of the seminiferous epithelium. The highlight of the talk was a Quick-time movie, dedicated to Lonnie, entitled "Symphony of Stages." This fascinating movie shows the Stages cycle as a dynamic process with cells dividing and germ cells moving into and out of the epithelium in time, all to the tune of a Russian Dance in the classical music of The Nutcracker. Plans are underway to make this CD available to the public, with proceeds used to establish an ASA fund in honor of Dr. Russell.
Wayne Vogl, Ph.D., from The University of British Columbia in Canada presented recent data on the role of ectoplasmic specializations and tubulobulbar complexes in sperm release and junction turnover. Ectoplasmic specializations, named by Dr. Russell, are unique actin containing adhesion junctions found in Sertoli cells at sites of intercellular contact. Recent results, reviewed by Dr. Vogl, indicate that the gelsolin-phosphoinositide pathway may be involved with actin filament disassembly in these structures during junction turnover. He also presented some preliminary data, from immunolocalization studies, consistent with the idea that tubulobulbar complexes may be involved with the internalization and degradation of adhesion components from sites previously occupied by ectoplasmic specializations. Tubulobulbar complexes were discovered by Dr. Russell who also suggested that they may play a role in junction turnover.
The third presentation focused on the Sertoli cell cytoskeleton, a subject to which Dr. Russell also made significant contributions. Kim Boekelheide, M.D., Ph.D., from Brown University in Rhode Island presented the thesis work of his graduate student, Shawna Fleming, in a session entitled "Sertoli Cell Microtubules: From Morphology to Function." In his presentation, Dr. Boekelheide described a novel molecular tool, adenoviral co-expression of gamma-tubulin and green fluorescent protein, which was used to specifically disrupt Sertoli cell microtubules in vivo. The resulting Sertoli cell dysfunction markedly altered the seminiferous epithelium, causing inhibition of spermatid translocation, spermatid release, and residual body phagocytosis, while increasing germ cell apoptosis. The presentation illustrated the power of combining morphological assessment and molecular tools to the in vivo dissection of complex cellular processes, such as Sertoli cell microtubule-dependent functions. Luiz Renata de Franca, Ph.D., from the Federal University of Minas Gerais in Brazil was ASA International Lecturer. His talk, “New Insights on Sertoli Cell Proliferation and Efficiency” nicely complemented the Spermatogenesis Symposium. Using pigs and fish as diverse animal models Luiz showed that regulation of Sertoli Cell proliferation and hence testis size by thyroid hormone (T3) is more complex than predicted based on evidence in the rat model. Bridging nutrition and male reproductive function, he also explained how leptin plays important roles in testis development. For example leptin knock out mice are infertile (with decreased testis and epididymal weight and decreased gonadotropins), but the condition can be reversed by giving back leptin.
Symposium II brought us up to date on Prostate Cancer. Nancy Weigel, Ph.D., from Baylor College of Medicine discussed her research on “Vitamin D and Prostate Cancer Growth” providing evidence that vitamin D inhibits the growth of prostate cancer cells in vitro. Interestingly, the extent of inhibition and recovery varies by cell line and is related to the presence of functional p53. Thus vitamin D or an analog may have potential as a future chemotherapeutic or chemopreventive agent. Ronald K. Ross, M.D., from the University of Southern California’s Norris Comprehensive Cancer Center discussed the “Epidemiology of Hormonal Effects on Prostate Cancer,” starting with the three major risk factors: age, family history, and race. Prostate cancer is an androgen dependent disease, and increased risks by race are associated with higher average serum testosterone levels that are also race-dependent. Genetic predisposition for prostate cancer is associated with polymorphisms in BRC 1 and 2, androgen receptor, and 5 alpha-reductase among others. Future genetic tests should allow high throughput screening for susceptible genotyes. Finally, Colleen C. Nelson, Ph.D., from the University of British Columbia in Canada told us about her work with gene arrays to characterize “Aberrant Gene Expression in Prostate Cancer Progression.” Her central hypothesis is that drift in gene expression occurs in tumors because it is adaptive in allowing tumors to survive. Initially androgen-dependent tumors are treatable by androgen ablation, but become resistant to this approach when they become androgen-independent with time. Her works shows that genotoxic stress leads to changes in gene expression such as YB-1 transcription factor entering the nucleus and turning on a gene cascade related to repair of damaged DNA. She is tracking changes in gene expression by tumors over time to determine specific genes and expression patterns associated with the transition to androgen-independence.
Symposium III centered on “Androgen Action in Human Health and Disease.” Christina Wang, MD, Professor of Medicine, Endocrinology, at Harbor-UCLA Medical Center in Torrance, California began the session by giving an “Update on Androgen Replacement Therapy”. She discussed the advantages and disadvantages of the currently available therapies, including the injectable esters, transdermal patches, transdermal gels, and implantable pellets. Then she went on to discuss new testosterone delivery modalities that may be available commercially within the next few years. These newer forms of testosterone delivery include buccal (through adhesion to the gum), sublingual, long acting injectable esters (months duration per injection), and 7-methyl-19-nortestosterone (MENT). MENT is somewhat more selective than testosterone in that it can be aromatized but is not available for 5-reduction; this potentially would result in the compound being less active in the prostate. At the current time, MENT is delivered as a subcutaneous implant, but in the future it is hoped that a transdermal method may be developed for its delivery. It was mentioned that other selective androgen receptor modulators (SARMs) are also under current development, but no data are yet available on these compounds. The second presentation, “Androgen Actions in Muscle Metabolism” was by Randall Urban, M.D., Professor and Chief of Endocrinology at the University of Texas Medical Branch, Galveston, Texas. He spoke about the clinical problems of sarcopenia, loss of muscle, which can occur with HIV wasting, severe burns or trauma, during space travel, with prolonged bed rest, or with normal aging. Androgens are anabolic and can help prevent muscle loss in many of these conditions. Androgens appear to promote synthesis of new muscle and have been shown to increase intramuscular IGF-1 levels. He then discussed one of his recent studies in older men and women, the data from which suggest that androgen action in muscle may be less effective with prolonged use; his group is beginning to explore the muscle effects of cyclic use of androgens. The final speaker was Monique Cherrier, Ph.D., Assistant Professor of Psychiatry at the University of Washington in Seattle. She began her presentation, “Androgen Effects on Cognitive Function in Humans”, reviewing some of the effects of sex steroids in the brain, including animal studies on effects of gonadectomy on axon density, synapse number, neurotransmitters, and metabolic activity in specific areas of the brain. Male rats made hypogonadal show increased dopamine in the prefrontal cortex, decreased synapses in the hippocampus, decreased ability to learn appropriate avoidance in a T-maze learning task, and increased anxiety. With testosterone replacement, these changes normalized, even in older animals. She also described her studies in older men which have shown that testosterone can improve spatial memory and verbal memory (story recall) compared to placebo treatment.
Symposium IV on “Environmental Influences on Human Semen Quality” began with a talk on “Pesticides and Semen Quality: Evidence of a Link from the Study for Future Families,” by Shanna H. Swan, Ph.D., from the University of Missouri. Since 1998, Shanna has led a multi-center team of scientists examining semen quality from four areas of the U.S. Based on the observation that sperm counts and total motile sperm counts were lower in men from Missouri (rural) compared with men from Minneapolis (urban), she hypothesized that pesticide exposure might account for this difference. After obtaining internal measures of exposure to a number of pesticides, she was able to show an association between exposure to certain pesticides and increased risk of having poor semen quality. Such data provide fertile ground for future studies linking exposure to effect. Steve Schrader, Ph.D. from the National Institute of Occupational Safety and Health (CDC/NIOSH) in Cincinnati, Ohio followed with a talk about “Occupational Exposures and Altered Semen Quality: What are the Risk Factors?” Using examples from human studies at NIOSH and elsewhere, he provided useful insights on how governmental agencies estimate risk and regulate chemicals and allowable exposures accordingly. Resources on this topic are available at http://www.cdc.gov/niosh and a pocket guide to hazardous chemicals is available in CD format from NIOSH upon request (Publication No. 2002-140, June 2002). Finally, Gary Klinefelter, Ph.D. from U.S. EPA in North Carolina relayed the “Saga of a Novel Sperm Biomarker: Discovery to Proof of Concept.” The sperm protein SP-22, which Gary found to be diminished in sperm from rats treated with a variety of epididymal and testicular toxicants, localizes to the sperm head. Antibodies to SP-22 and recombinant SP-22 inhibit fertilization in vitro and in vivo, and cross react with sperm of many species. Efforts are underway to explore the association between SP-22 in human sperm and infertility, which could lead to improved fertility assays applicable to the diagnosis of infertility, and to toxicology testing. Additional plenary lecturers included Mary M. Lee, M.D., from Duke University in North Carolina, who gave the ASA Women in Andrology Lecture on “Mullerian Inhibiting Substance: Role in Sexual Differentiation and Gonadal Development.” One of the first proteins expressed in testis development, MIS is necessary for normal development of the male but not female tract (knock out mice have retained Mullerian ducts, foci of Leydig Cell hyperplasia, focal tubule atrophy and infertility) while over-expression in adults is detrimental in both sexes. Using EDS to kill Leydig Cells, she then showed that MIS can inhibit Leydig Cell regeneration and down regulate steroidogenesis. Using microarray analysis she is studying MIS regulated genes in Leydig Cells and other reproductive cell types. Clinically she is using MIS to help diagnose gonadal disorders especially in cryptorchid newborns and virilized girls, and as a tumor marker.
Laura Schieve, Ph.D., from the Centers for Disease Control (CDC) in Atlanta, Georgia, updated us on “Risks for Adverse Birth Outcomes after Assisted Reproductive Technologies.” Births from ART are expected to exceed 1% of live births in the US based on data for 2001 so there is sufficient data to begin to explore risk factors. Her analyses of data from 383 clinics reporting in 2000 provide demographics of women using all types of ART procedures and respective success rates. Risks for multiple births (about 35% of ART pregnancies) include: the type of ART, patient’s age, number of embryos transferred and number of embryos available for transfer. ART also poses risks for low birth weight and preterm infants even after controlling for other factors thought to predispose for low birth weight or prematurity. Risks for chromosome aberrations are increased for ICSI cases, as is risk for hypospadias, although in these cases it is not clear if the risk stems from the ART treatments or is related to the underlying infertility. On the other hand, the good news is that risks for childhood cancer and other developmental problems do not appear to be associated with ART.
Sally Perreault (Program Chair), Arnold Belker, Rex Hess and Lisa Tenover