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Abstract
At the International Symposium and Forum on Endocrine and Molecular Interventions in Aging, participants discussed therapeutic applications of DHEA, testosterone, and estrogen, and looked at responses to IGF-1, melatonin, and antioxidants.
The International Symposium and Forum on Endocrine and
Molecular Interventions in Aging was held March 7-11, 1998 in Tampa,
Florida. Participants, emphasizing their role in preventing or modifying the
effects of age, discussed potential benefits in
therapeutic applications of dehyroepiandrosterone (DHEA), the
positive and negative effects of testosterone and estrogen
replacement therapies, and looked at responses to insulin-like
growth factor 1 (IGF-1), melatonin, and antioxidants.
Testosterone Replacement Therapy: Pros and Cons Will androgen replacement therapy reverse some of the
changes associated with aging? asked William Bremner of
the Department of Veterans Affairs Health System and professor of medicine at the
University of Washington School of Medicine in
Seattle. Can it be as beneficial as estrogen replacement for post-menopausal
women? The answer is both yes and no. Bremner outlined what we know about testosterone's roles. It
preserves bone mineral content and reduces fat while promoting
lean body mass - two pluses that could lead to fewer fractures in
elderly men and could prevent cardiovascular diseases and diabetes.
When Bremner put two groups of men whose average age was 67 on
alternating testosterone treatments, he found that injected
testosterone increased their libido and overall health.
"They knew which arm of the study they were on based on how
they felt," Bremner said.
Monique Cherrier (Puget Sound Veterans Administration, Washington), a research associate
of Bremner's, recently found that testosterone replacement had a
beneficial effect on spatial and verbal memory in elderly men.
Her work may have application in treating Alzheimer's disease.
"Testosterone's effects are presumably mediated through the
androgen receptor, which is widely but selectively distributed
throughout the brain," Cherrier said. "The hippocampus and medial
temporal regions, which underlie certain spatial abilities, are a
particular target for gonadal hormones and demonstrate neural
growth in response to androgen release. These same brain regions
are affected by Alzheimer's disease." Increasing evidence that testosterone replacement therapy
can have many of the same benefits as estrogen replacement
therapy for women continues to fill the professional and lay
literature. Bremner pointed to a study, discussed in the January
16, 1998 issue of Science, that looked at weight gain and
diminished testosterone. "A well-controlled, pilot clinical trial of testosterone
replacement in elderly men has reported encouraging results,"
Bremner said. "This study reported improvements in muscle mass,
bone, sexual function, and LDL levels. The two areas of greatest
concern in considering the role of testosterone replacement in
the elderly are effects on the prostate and cardiovascular
disease." Peter Snyder (University of Pennsylvania Health System) elaborated on
the risks associated with what may at first look like a fountain
of youth for elderly men. "The risks and benefits must be weighed," Snyder said. "We
have to consider the possibility that treating with testosterone
could contribute to clinically significant prostate cancer."
In drawing the link between natural amounts of testosterone
and prostate cancer, Snyder pointed to a study of blood samples
taken in 1982 from physicians who were then between the ages of
40 and 84. When the samples were analyzed 15 years later,
researchers found that higher testosterone levels in 1982 were
associated with a 2.5 times greater chance of developing prostate
cancer. "Testosterone predicted prostate cancer in that study," said
Snyder, who fears side effects to testosterone replacement:
prostate enlargement, prostate cancer, sleep apnea, increased
hypercoagulability, and an unidentified effect on lipids. Snyder discussed the paradox presented by an
apparent relationship between testosterone and prostate cancer in
elderly men. Why, he asked, when testosterone is reaching its
lowest level, after age 60, does it appear to cause prostate
cancer? "I can't explain it," he said. "But my guess is that
there is still sufficient testosterone to play a role in the
development of prostate cancer." Estrogen Replacement Therapy: Benefits and Risks While cardiovascular protection and increased bone density
have become clear benefits of postmenopausal estrogen
replacement therapy, and its potential for lowering the risk of
Alzheimer's disease is being explored, cloudy still is the
relationship between long-term estrogen replacement therapy - more
than three years - and the development of breast cancer. Risk
begins to appear at five years.
"Short-term hormone replacement therapy in postmenopausal
women is effective for the treatment of estrogen-deficient
symptoms of vasomotor flushes and vaginal dryness," said Kathryn
Martin (Harvard Medical School). "No study has demonstrated
an increased risk of breast cancer with short-term use.
Therefore many, if not most women, except those with a history
of breast cancer, are candidates for short-term treatment for
symptomatic relief."
Martin added that while there are concerns about adding
progestins to estrogen replacement therapy - necessary to prevent
endometrial complications in women with a uterus - progestin does
not appear to reduce estrogen's beneficial affects on the heart.
Graham A. Colditz (Harvard School of Public
Health) said that non-cancer-causing strategies for the relief of
menopausal symptoms and long-term prevention of osteoporosis and
heart disease are "urgently needed." "The magnitude of the increase in risk of breast cancer per
year of use of hormones is comparable to that of delaying
menopause," he said. He concluded by saying, "The decision to use
estrogen replacement therapy must be an individualized one. It
should be based on each woman's medical history and personal
choice." Can DHEA Replacement Keep Us Young? Plasma concentrations of dehyroepiandrosterone (DHEA), a natural hormone, decrease
over time in both men and women, said Etienne-Emile Baulieu
(INSERM, France). While DHEA has become a popular over-the-counter item
and its pros and cons are discussed in the mass
media, Baulieu said that its affect on the prostate and its
relationship to other hormones, such as testosterone, are
unclear. While DHEA supplementation remains controversial, William
Regelson (Medical College of Virginia) said that DHEA
demonstrates antitumoral activity, can be used to treat lupus,
and has appeared in "clinical anecdotal reports" as being of
value in treating myeloma, lymphoma, and pancreatic and renal
cancer.
"Adequate clinical studies are needed - alone and in
conjunction with chemotherapy," said Regelson, who has been
taking DHEA for twelve years and is unhappy that because DHEA is
a naturally occurring hormone, it will not be approved by the FDA in the near future.
"Its clinical safety has been established, as it has been available as Prasterone in Europe
for menopausal treatment for some twenty years," he said. He added that
DHEA enhances viral and bacterial infection resistance, is an effective antidepressant, and can
reverse chronic fatigue.
"Instead of being intimidated by the over-the-counter
availability of DHEA, we physicians should insist that our
patients join with us in establishing baseline values governing
hormone replacement and therapeutic application," Regelson
concluded.
Melatonin and Aging "The effects of melatonin on cellular physiology may be
related to aging in a number of ways," said Russel J. Reiter (University of Texas).
"Melatonin has been shown to be
an effective scavenger of the highly toxic hydroxyl radical as
well as detoxifying singlet oxygen, the peroxyl radical, the
superoxide anion radical, and the peroxynitrite anion.
Additionally, melatonin stimulates antioxidative enzymes. Since
free radicals are believed to play a prominent role in both aging
and a variety of age-related diseases, melatonin's potential
effects in delaying these processes is apparent." Reiter added that there is no
"definitive proof" that
melatonin has a function in determining the rate of aging or the
longevity of organisms, and that tests of melatonin supplements
have not been "uniformly successful." Walter Pierpaoli (INTERBION Foundation for Basic Biomedical Research, Bellinzoma, Switzerland)
discussed his studies of night administration of melatonin to
mice in which the animal models "postponed" their aging, delayed
the onset of autoimmune disease, and increased resistance. His
success with animal models lead him to speculate on the age-preventing
properties in melatonin.
"We have conducted extensive investigations aimed at
possibly understanding the mechanism by which melatonin can
correct practically all age-related derangement measured,
including immunity, mineral levels, lymphocytes, testosterone,
corticosterone, cholesterol and others," Pierpaoli said. "We are
confident that our models in vivo will allow us to progressively
elaborate the methods and to identify vehicles that allow for
maintaining perfectly synchronized neuroendrocine and immune
functions, and to prevent aging-related diseases such as
cardiovascular, autoimmune diseases, and cancer."
Reiter cautioned against overoptimism.
"The role of melatonin, if any, in the process of aging and
the development of age-associated disease, must await further
experimentation," he said.
Antioxidants and Reducing Oxidative Stress "The free radical theory of aging," said Jeffrey Blumberg (Tufts), "hypothesizes that the
degenerative changes associated with aging might be produced by
the accumulation of deleterious side reactions of free radicals
produced during cellular metabolism and generated in vivo by
environmental exposure to pro-oxidant radicals." At the cellular level, oxidation of amino acids can cause
cell damage, and at the DNA level, oxyradical-induced DNA cross
links could lead to somatic mutations and loss of essential
enzyme expression, he added. Daily oxidative hits are generally
repaired quickly, but small numbers of unrepaired lesions caused
by inadequate antioxidant defenses could cause permanent DNA
changes. Blumberg concluded that understanding how antioxidants
reduce oxidative stress offers opportunities for health promotion
- via diets rich in antioxidants - and the treatment of chronic
disease. According to Blumberg, recent studies have shown that
high antioxidant intake may reduce risks for age-related
conditions and diseases such as atherosclerosis, cancer,
Parkinson's disease, and Alzheimer's disease.
Growth Hormones and Aging A research team from the Research Center for Endocrinology
and Metabolism, Sahlgrenska University Hospital, Goteborg,
Sweden, suggested that there are "striking similarities" [in
obesity and insulin resistance] between the "metabolic syndrome"
(syndrome X) and untreated growth hormone (GH) deficiency in
adults. Their nine-month trial of GH treatment reduced total body
fat, improved insulin sensitivity, improved diastolic blood
pressure, and suggested a potential role for GH in treating
cardiac irregularities.
"In GH deficient adults who receive GH substitution therapy,
an improvement in systolic function and normalization of left
ventricle mass has been found," said team member Bengt-Ake Bengtsson.
The group also found that after six months of GH therapy,
elderly patients on dialysis improved their lean body mass,
muscle strength, and walking capacity.
Randolph Fillmore is a freelance medical technical writer and science journalist who has written for Faulkner and Gray, Prudential Health Care, Stars and Stripes, and The Baltimore Sun.
The illustration is a detail from Thomas Moran, Ponce de Leon in Florida, 1878, evoking the explorer's legendary search for the Fountain of Youth.
Journal of Anti-Aging Medicine - premiered at the symposium. The new journal will reportedly "provide a common meeting ground, a venue, and perhaps a sense of
community . . . for dreamers, skeptics, pragmatists, all sharing a common suspicion that we can understand aging . . . a common intent that we can alter it, and a common hope that it will benefit us all."
Endocrine Society - meets June 24-27, 1998, in New Orleans. Society for Endocrinology Electronic Journals
- publishes the Journal of Endocrinology, the Journal of Molecular Endocrinology, and Endocrine-Related Cancer. The full text of the last
journal is freely available online, and abstracts of the combined journals may be searched.