Center scientists are closing in on the origins of polycystic ovarian syndrome (PCOS), a multi-symptom disease that affects as many as one in 15 women in the United States. Despite its prevalence, the syndrome is not well known or understood by the general public and the clinical community alike.

David Abbott, Ph.D., and Mayo Clinic co-principal investigator Daniel Dumesic, M.D., were the first to discover that, even though symptoms do not appear until puberty, PCOS is programmed in the fetus during the second trimester of pregnancy. In 90 percent of all cases, PCOS is characterized by a telltale “ring of pearls” grouping of small cysts within the ovaries. Polycystic ovaries, as well as infertility, high testosterone and high insulin levels, are the trademarks of this disease. Women in their 20s and 30s with PCOS are at great risk of developing life-threatening early-age diabetes. 

Other symptoms may include hirsuitism (excess body hair) and obesity (particularly abdominal fat). Even women with PCOS who do not develop diabetes may face each day with great discomfort at best. This may include low self-esteem, or even depression, due to the undesirable visible effects on their bodies, as well as their inability to conceive.

“A fifth of all normal women have multiple follicular cysts in their ovaries, but aren’t infertile, hirsute or obese. It turns out that most are hyperandrogenic,” Abbott clarified. “So, polycystic ovaries commonly occur with high androgen levels. But to actually have PCOS, you also need high insulin levels. It’s the high insulin that brings in anovulation and precedes diabetes.”

With all these different symptoms, Abbott explained, it took a while for clinicians to identify PCOS as more than infertility. It is now recognized as a tremendous problem in women’s health.

“PCOS is likely the largest single cause of infertility in women,” he said. “The reason it hasn’t shown up historically is because only a small portion of women with the disease actually visited infertility clinics.” The rest, he explained, were being treated for diabetes, hirsuitism, obesity and other problems. “In the late 1980s, clinicians were still trying to understand the full extent of the entity we call PCOS,” he added. “Now, many more clinicians cross-refer, and catch more of the specific pathologies that will define PCOS. Many primary care physicians, however, still miss catching PCOS, as patients can present with only one pressing health concern that does not in itself herald PCOS, unless the physician follows up.” 

Now a full professor of obstetrics and gynecology at UW-Madison, Abbott began working with his group of female rhesus macaques a decade ago. Originally from Edinburgh, Scotland, he was working at the London Zoo when a joint faculty position in Ob/Gyn and the Primate Center opened in 1990. Because rhesus monkeys have similar ovarian and metabolic physiology to humans, Abbott recognized that they would be perfect for pursuing PCOS studies, one of his growing research interests. PCOS had been a recognized disorder since the 1920s, when it was named Stein-Levanthal Syndrome after the two clinicians who first identified its phenotype.

After coming to Wisconsin, Abbott teamed up with Dumesic to hypothesize that hyperandrogenism, or too much testosterone, early in development may be the root cause of PCOS. The Wisconsin Regional Primate Research Center had a unique population of rhesus monkeys that could provide a key answer. In carefully controlled studies, pregnant monkeys were exposed to high levels of testosterone, particularly during their second trimesters. Sixteen to 22 years later, a large number of the female babies born have developed PCOS as adults. The PCOS monkeys were originally produced by Dr. Robert Goy, director of the Primate Center from 1971 To 1989, for his ground breaking studies in hormonal differentiation of socio-sexual behavior.

“For the first time, these monkeys allowed us to catch a glimpse of possibly the primary source of the problem,” Abbott said. “This is testosterone excess during early life.”

Abbott, Dumesic and Dee Schramm, Ph.D., who has recently joined them as a co-investigator on PCOS studies, are part of worldwide efforts to tackle this puzzling disease. They are working together to provide basic scientific data and apply their knowledge to clinical studies of women at the Mayo Clinic. They have come a long way in helping women diagnose their disease. Patients can better understand their affliction, learn what to expect from possible treatments, and realize that they have strong advocates who are working toward a cure.

Dumesic is participating in a multicenter study that is examining the effects of d-chiro-inositol, a new insulin sensitizing agent, on ovulation, blood pressure and circulating androgen as well as lipid levels.

But the team is facing one roadblock in its quest for PCOS enlightenment: The monkeys in the study are 16 to 29 years old. They enter menopause between age 25 and 27.

“These are the last prenatally androgenized monkeys at the Primate Center,” Abbott frequently tells news reporters and convention audiences. “We need to produce the next generation to meet the challenge of PCOS.”

Abbott is gratified that he has helped women understand some of the new thinking about the origins of their syndrome and how future approaches may combat PCOS development in addition to the current clinical approach of ameliorating the adult symptoms. “I’m so heartened with this opportunity to use our monkey model to help shape clinical thinking and future treatment of PCOS.”

Additional collaborators on the center’s PCOS studies include Ricki Colman, Ph.D., Joseph Kemnitz, Ph.D., and Joel Eisner, B.S., Ted Goodfriend, M.D. at UW-Madison, Vasantha Padmanabhan, Ph.D., at the University of Michigan, Robert Rosenfield, M.D., at the University of Chicago, Alan McNeilly, Ph.D., D.Sc., at the University of Edinburgh, and Steve Franks, M.D., at the University of London, UK.

More information:
• Polycystic Ovarian Syndrome Association Inc.
 http://www.pcosupport.org.
• University of Chicago PCOS Center
 http://centerforpcos.bsd.uchicago.edu
• For women with PCOS in Wisconsin
 http://wisconsin@pcosupport.org.

References:
Eisner, J.R., D.A. Dumesic, J.W. Kemnitz and D.H. Abbott. 2000. Timing of prenatal androgen excess determines differential impairments in insulin secretion and action in adult female rhesus monkeys. J. Clin. Endocrinol. Metab. 85: 1206-1210.

Abbott D.H., D.A. Dumesic, J.R. Eisner, R.J. Colman and J.W. Kemnitz. 1998. Insights into the development of PCOS from studies of prenatally androgenized female rhesus monkeys. Trends in Endocrinology and Metabolism 9:62-67.

Primate Center Library receives major NIH grant

The library at the Wisconsin Regional Primate Research Center has received a major grant from the National Institutes of Health to promote Internet access to primatological resources. The award is one of the largest NIH grants ever awarded to a primate center library.

The $2.5 million, five-year grant from the National Center for Research Resources will boost the library’s staff and resources so that it can more effectively work with other NIH primate centers and the international primatological research community.

“This is a unique and challenging opportunity to use the World Wide Web to deliver information services to the broad primatological research community,” said Chief Librarian Larry Jacobsen. “It builds on the strengths of UW-Madison Libraries—their collections, expertise and commitment—to share research findings and resources with an international audience.”

Specifically, the grant will allow the library to work cooperatively with the Primate Centers to coordinate information services for research and affiliate staff and to promote information sharing. Included will be coordination of collections; rapid sharing of information among the centers through electronic document transfer; development of a centralized information services menu; establishment of the Primate Information Center's (PIC) PrimateLit database as a freely available Web-based resource; development of Primate Info Net (PIN) as an Internet access tool; and sharing of research and educational expertise of RPRC staff with the scientific community and general public.

This fall, PIC’s PrimateLit database will move from the University of Washington  to the University of Wisconsin-Madison. The GLS’s Library Technology Group will provide  Web-based public access and technical support. PIC will continue to index the primatological literature through a subcontract with the WRPRC.
 

New External Advisory Board appointed

The WRPRC has appointed its new external advisory board. This board met for the first time Oct. 19-20 to 
 help staff plan for the five-year base grant renewal. Members include Jeanne Altmann, Ph.D. (Princeton University); Joseph Bielitzky, M.S., D.V.M. (NASA, Ames Research Center); George Bray, M.D. (Pennington Biomedical Research Center, Louisiana State University), Molly Carnes, M.D. (UW-Madison), Rodney Phillips, M.D. (Oxford University); Eric T. Poehlman, Ph.D. (University of Vermont); Arnold Ruoho, Ph.D. (UW-Madison); Bill Scanlon, Ph.D. (Scanlon Law Office, Madison); and Jerome Strauss III, M.D., Ph.D. (University of Pennsylvania).

WRPRC Research Highlight

How is the fetus protected from immune rejection by the mother, since half of its genes have been inherited from the father?

This has long been a key question asked by reproductive and developmental biologists . Now, researchers at the Wisconsin Regional Primate Research Center are closing in on the answer.

According to new research from the lab of Ted Golos, Ph.D., the presence of specialized molecules on the surface of rhesus monkey placental cells at the time of implantation provides evidence of an important role for MHC class I molecules in the establishment of a successful pregnancy.

Golos, Igor Slukvin, Ph.D., David Watkins, Ph.D., and others identified Mamu-AG as a unique MHC class I molecule (a type of transplantation antigen) that shares many characteristics of a human placental molecule known as HLA-G. 

“The true function of the human molecule remains unknown because of the inability to test hypotheses experimentally in women,” Golos explains. “So the monkey is an invaluable model to examine the importance of this molecule in establishing and maintaining pregnancy.”

Since the Mamu AG molecule is hypothesized to modulate the maternal immune system, additional potential significance may be in transplant biology. “There is interest in HLA-G in the context of organ transplantation,” Golos says. 

Scientists cannot study the interactions of the maternal immune system with the placenta without using pregnant animals. “We are using the rhesus monkey because its immune system and MHC molecules and most importantly,  the structure and function of its placenta are very similar to that in humans,” Golos says.

The nonhuman primate model also allows researchers to look at the very earliest time during pregnancy, the implantation stage, when the most critical events for the establishment of pregnancy are occurring.

“This is the time when most embryonic loss occurs in humans, yet this very early time in pregnancy cannot be directly studied with human clinical samples.”

Reference:
Slukvin, II, Lunn, DP, Watkins, DI, Golos, TG. 2000. Placental Expression of the nonclassical MHC class I molecule Mamu-AG at implantation in the rhesus monkey. PNAS.
 

International directors tour Primate Center

Special guests from Puerto Rico and abroad joined the directors of the eight NIH-NCRR Primate Centers during their biannual meeting in Madison Oct. 4.

Dr. Edmundo Kraiselburd, director of the Caribbean Primate Center in San Juan, Puerto Rico, shared his goals for promoting more biomedical research and research collaborations at his center.

Dr. Gerhard Hunsmann, director of the German Primate Center in Göttingen, discussed his center’s main focus in virology and immunology, as well as his goals for studying spongiform encephalitis, also known as Mad Cow Disease.

AIDS, hepatitis, parisitology, malaria, multiple sclerosis and rheumatoid arthritis constitute ongoing studies at the Biomedical Primate Research Centre in Rijswijk, Netherlands, directed by Dr. Ronald Bontrop.

The Medical Primatology Center, directed by the same man, Dr. Boris Lapin, for nearly 50 years, almost didn’t survive the early 1990s, when several Balkan states split off from Russia to claim their independence. After 5,000 of his monkeys and several scientists were killed or unaccounted for, Dr. Lapin, who narrowly escaped arrest himself, relocated his center from Georgia to Sochi, Russia. His focus remains on studying leukemia and lymphoma.
 

Just published

Center scientists and affiliates publish frequently in peer-reviewed scientific journals. Following is just a small 
sampling of recent abstracts from these publications, reprinted here with  permission.

Vogel TU, Dunphy E, Liebl ME, Emerson C, Wilson N, Kunstman KJ, Wang X, Allison DB, Hughes AL, Desrosiers RC, Altman JD, Wolinsky SM, Sette A, Watkins DI.  Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature. 2000 Sep 21;407(6802):386-90.

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by early peaks of viremia that decline as strong cellular immune responses develop. Although it has been shown that virus-specific CD8-positive cytotoxic T lymphocytes (CTLs) exert selective pressure during HIV and SIV infection, the data have been controversial. Here we show that Tat-specific CD8-positive T-lymphocyte responses select for new viral escape variants during the acute phase of infection. We sequenced the entire virus immediately after the acute phase, and found that amino-acid replacements accumulated primarily in Tat CTL epitopes. This implies that Tat-specific CTLs may be significantly involved in controlling wild-type virus replication, and suggests that responses against viral proteins that are expressed early during the viral life cycle might be attractive targets for HIV vaccine development.

* * * 

Zainal TA, Oberley TD, Allison DB, Szweda LI, Weindruch R. Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle. FASEB J. 2000.Sep;14(12):1825-36.

In laboratory rodents, caloric restriction (CR) retards several age-dependent physiological and biochemical changes in skeletal muscle, including increased steady-state levels of oxidative damage to lipids, DNA, and proteins. We used immunogold electron microscopic (EM) techniques with antibodies raised against 4-hydroxy-2-nonenal (HNE) -modified proteins, dinitrophenol, and nitrotyrosine to quantify and localize the age-dependent accrual of oxidative damage in rhesus monkey vastus lateralis skeletal muscle. Using immunogold EM analysis of muscle from rhesus monkeys ranging in age from 2 to 34 years old, a fourfold maximal increase in levels of HNE-modified proteins was observed. Likewise, carbonyl levels increased approximately twofold with aging. Comparing 17- to 23-year-old normally fed to age-matched monkeys subjected to CR for 10 years, levels of HNE-modified proteins, carbonyls, and nitrotyrosine in skeletal muscle from the CR group were significantly less than control group values. Oxidative damage largely localized to myofibrils, with lesser labeling in other subcellular compartments. Accumulation of lipid peroxidation-derived aldehydes, such as malondialdehyde and 4-hydroxy-2-alkenals, and protein carbonyls were measured biochemically and confirmed the morphological data. Our study is the first to quantify morphologically and localize  the age-dependent accrual of oxidative damage in mammalian skeletal muscle and to demonstrate that oxidative damage in primates is lowered by CR.

* * * 

Saltzman W, Prudom SL, Schultz-Darken NJ, Abbott DH. Reduced adrenocortical responsiveness to adrenocorticotropic hormone (ACTH) in socially subordinate female marmoset monkeys. Psychoneuroendocrinology 2000 Jul;25(5):463-77.

Socially subordinate female common marmoset monkeys undergo pronounced, chronic reductions in basal plasma cortisol levels, which appear to result both from socially induced suppression of reproductive hormones and from direct effects of social subordination. In this study, we tested the hypothesis that this cortisol suppression is mediated by reduced adrenocortical responsiveness to adrenocorticotropic hormone (ACTH). Dominant, subordinate, and ovariectomized females were given dexamethasone (5 mg/kg, IM), followed the next morning by human ACTH(1-39) (10 microg/kg, IV) or sterile saline (0.5 ml/kg, IV); blood samples were collected at -20 through 150 min from ACTH or saline treatment and assayed for cortisol. ACTH, but not saline, caused a marked elevation of plasma cortisol levels. Prior to ACTH treatment, dominant females tended to have higher dexamethasone-suppressed cortisol levels than subordinate and ovariectomized females. After ACTH treatment, dominant females had significantly higher cortisol concentrations, as well as higher peak and net integrated cortisol responses to ACTH, than did subordinate and ovariectomized animals; the latter two groups showed comparable cortisol responses to ACTH. These results suggest that dampened adrenocortical responsiveness to ACTH contributes to chronic reductions in cortisol levels in subordinate female marmosets and may be mediated by suppression of reproductive hormones.

Gleanings
 

New grants
Ruth Benca, Ph.D., and Ned Kalin, M.D., have received a new, four-year NIH grant titled, “The Amygdala and Primate Sleep.”

Jon Ramsey, Ph.D., has been awarded a four-year $750,000 grant from NIA to study mitochondrial energy metabolism in the contexts of aging and dietary restriction.

Mary Schneider, Ph.D., at the Harlow Center for Biological Psychology has received an 18-month grant from the Wallace Foundation entitled, “A primate model of sensory modulation disorder.” 

David Watkins, Ph.D., on July 1 was awarded a five-year NIH grant entitled, “MHC-bound SIV-derived CTL and HTL epitopes.” With this new grant, the Watkins laboratory aims to further develop the rhesus macaque as an animal model for HIV vaccine discovery.

Researchers earn long-term renewals
“The Development and Regulation of Emotion in Primates” is the title of a NIMH renewal grant awarded to Ned Kalin, M.D. Co-investigators include Richard Davidson, Steve Shelton, and Andy Roberts. This renewal represents the 10th grant year of this work.

Ei Terasawa, Ph.D., has received two five-year grant renewals from the NIH-NICHD. “The Hypothalamic Control of Puberty” has been awarded its 19th through 23rd grant years. “The Hypothalamic Control of Gonadotropin Secretion” will begin its 17th through 21st  grant years.

Honors
Rick Weindruch, Ph.D., received two prestigious national research awards in 2000. The first was the Harman Research Award given by the American Aging Association to recognize outstanding achievement in the field of gerontology. The second was the Nathan W. Shock Award, presented annually by the National Institute on Aging to highlight outstanding work in the field of aging research. Weindruch, who joined the UW faculty in 1990, has studied caloric restriction and aging for more than 25 years.

Promotions
Daniel Dumesic, M.D., was promoted to full professor of obstetrics and gynecology at Mayo Medical School, Rochester, Minnesota, on Sept. 12. Dan, who collaborates with David Abbott, Ph.D., and Dee Schramm, Ph.D., in polycystic ovarian syndrome research at the center, has been a physician and researcher with the Mayo Clinic since 1994. He is also chair of the Department of Obstetrics and Gynecology, and a consultant for the Division of Reproductive Endocrinology at the Mayo Clinic.

Masaharu Mizuno, Ph.D., was promoted from research associate to assistant researcher  in Dr. Ei Terasawa’s lab.

In the news
Todd Allen, Ph.D., David O’Connor, B.Sc., and David Watkins, Ph.D., made front page headlines Sept. 21 after their research on SIV vaccine development was published in Nature. They showed for the first time, using a nonhuman primate model, that the AIDS virus avoids the body’s strongest immune responses during the first few weeks of infection. The finding opens the door to new vaccine directions.

Richard Atkinson, Ph.D., remarked in the Sept. 5 Washington Post, “It has been hard to convince some skeptics that some forms of obesity may be caused by a virus.” Yet results from campus studies performed by Atkinson and Nikhil Dhurandhar, Ph.D., reveal evidence that chickens, mice and monkeys grow fat when injected with a human adenovirus known as Ad-36. Data from human studies are pointing toward the possibility that the virus causes obesity in people as well.

The polycystic ovarian disease research of David Abbott, Ph.D., and Dan Dumesic, Ph.D., was covered in a sidebar to a feature story on a patient living with the disease in the Wisconsin State Journal July 16. The story and sidebar were titled, respectively, “PCOS: Strange disease sends self esteem reeling” and “UW researcher leads charge against PCOS.”

A great deal of media attention this year was focused on Ned Kalin, M.D., and Richard Davidson, Ph.D. Madison Magazine and On Wisconsin highlighted their work in scientifically defining a connection between positive emotion and mental and physical health. Madison’s weekly newspaper Isthmus described Dr. Davidson’s research into the effects of meditation in treating depression. The two were also featured in a Discover magazine article, “Wired for sadness,” and in a Wisconsin Week article, “Pursuing happiness ? scientifically.” The latter publication was reporting on the sixth annual Wisconsin Symposium on Emotion, held in Madison April 13-14 and titled, “The Neurobiology of Positive Emotion.”

Joseph Kemnitz, Ph.D., and rhesus monkeys in the aging and dietary restriction studies appeared on Milwaukee’s WTMJ TV News June 22 and 23.  The NBC affiliate station’s feature was titled, “Fountain of Youth.”  Dr. Kemnitz also spoke about the use of animals in research June 26 on Radio Health Journal, a syndicated program aired on 350 stations nationwide. Finally, he was interviewed by Wisconsin Public Radio May 3, on center studies on dietary restriction and aging in rhesus monkeys.

Dee Schramm, Ph.D., commented on nuclear transfer attempts by a team at Wake Forest University in the Winston-Salem Journal April 28. Dr. Schramm is trying to make genetically identical monkeys by splitting normal embryos into identical twins and triplets. The Wake Forest team is transferring genetic information from adult monkeys into embryos in an attempt to clone monkeys for alcoholism research.

Wisconsin Week published “Researchers tantalize animal taste buds” on April 19. Göran Hellekant, Ph.D., Vick-toria Danilova, Ph.D., and colleagues have perfected the “Taste-o-matic,” a machine that allows them to determine what monkeys and other animals taste based on a given oral stimulus. Any of 32 different taste solutions can tickle an animal’s tongue via the machine’s plastic tube.

The Milwaukee Journal-Sentinel Online March 21 featured the work of David Pauza, Ph.D., and the Immunology and Virology Core Lab in collaboration with the Institute of Human Virology.

New staff
Amy Allen, B.S., associate research specialist, June 1 (Saltzman lab).
David Williams Burleigh, Ph.D., research associate and postdoctoral fellow, June 1 (Golos lab).
Clay Glennon, B.S., information processing consultant, June 12 (Pathology Unit). 
Pat Hepner, B.S., payroll and benefits specialist, April 1 (Business Office). 
Takuo Kawamoto, Ph.D., Honorary Fellow, April 1 (Thomson lab).
Yi-Ping Liu, Ph.D., postdoctoral fellow and research associate, June 23 (Golos lab).
Rachel L. Lewis, B.S., research specialist, Aug. 1 (Thomson lab).
Watkins lab:
Jason S. Reed, B.S., associate research specialist, Sept. 1.
Kristin Schultz, B.A., associate research specialist, July 5.
Sanju Sridharan, B.S., associate research specialist, June 12. 
Jason Weinfurter, B.S., associate research specialist, Jan. 18. 

Departures
Laurie Abler, B.S., associate research specialist, June 9 (Terasawa lab).
Paul DuBois. M.S., senior information processing consultant, Aug. 29
C. David Pauza, Ph.D., senior scientist, June 30.
Maria Salvato, Ph.D., senior scientist, June 30.
Michelle Waknitz, research specialist, July 14,  (Thomson lab).
 

AIDS 2000

More than 240 scientists from nearly every continent met in Madison Oct. 4-7 for the 18th Annual Symposium on Nonhuman Primate Models for AIDS. The Primate Center hosted the symposium at Monona Terrace. David Watkins, Ph.D., was scientific program chair. Presentations addressed therapeutics, immunology, virology, pathogenesis, and technology and resource development. The keynote speaker was Andrew McMichael, Oxford University. The symposium planner was Edi Chan.
 

Primate Pathology Seminar
and Workshop 2000

Amy Usborne, D.V.M., and Iris Bolton, D.V.M., co-chaired the “Primate Pathology Seminar and Workshop 2000,” hosted by the WRPRC Oct. 7-8. Pathologists, clinical veterinarians and investigators from the NCRR Primate Centers and other facilities shared case presentations with 30 attendees at the Pyle Center on the UW-Madison campus. Dr. Robert Garrison from the State Laboratory of Hygiene in Madison gave a short lecture, “Parasites in Wild Caught Primates.” During the dinner lecture at the University Club, guest speaker Dr. Stephen Nash, of Conservation International and State University of New York, presented “Primates in Pictures.” He spoke on the use of primate images throughout history, to their present use as a flagship species in conservation education campaigns. Dr. Nash is collaborating on a project with the WRPRC Library that will significantly increase primate art and illustration images in the Library's Audiovisual Archive.

Primate Center hosts Fall, Spring Seminar Series

More than 200 speakers have given informative presentations to staff and affiliates since the Primate Center Seminar Series began in the mid 1980s. Conference organizers over the years have included center scientist Gary Davis, Phillipa Claude, Ted Golos, Wendy Saltzman, Jon Ramsey, Dee Schramm and David Abbott. We applaud their efforts!