Promoting the Fountain of
Youth: Low-T and Estrogen
Deficiency
Adriane Fugh-Berman MD
Georgetown University Medical Center ajf29@georgetown.edu
Hormone Therapy in Women
• Animal glandulars became popular in the 1890s
• First recorded menopausal HT
– Administration of cow ovaries to a young
oophorectomized woman in Berlin circa 1900
• In the U. S.
– Fresh, ground ovaries first used in 1910
– Later, desiccated and then extracted preparations
The Estrogen Era
• 1920s: Estrone (theelin)
isolated from pregnant women • 1928: Progynon (from human
placenta)
• 1933: Progynova (estradiol)
• 1938: Ethinyl estradiol
• 1942: Premarin (conjugated
1959
“Difficult family situations can often be wholly
remedied by estrogen therapy for the woman involved.”
JAMA July 1, 1968; 205(1):8
“Expand Menopause”
• 2002: $5.5 million was budgeted in the United
States to expand the definition of menopause.
– $3.7 million was devoted to developing “long-term
benefits.”
• Wyeth aimed to convince physicians and
consumers that “estrogen deficiency” not only caused unattractiveness and ill-health, but also an early death.
Persuading Women
• Wyeth coached physicians on how to “Present
the benefits of HRT ‘from top to bottom, brain to bladder.’...HRT offers multiple benefits for now and a better future”
• Physicians were encouraged to provide
“Personal anecdotes: Mother, wife’s
experience of menopause/HRT; What I would/ did do; Coaxing: only need to make a
HERS: Second CHD Events
*P=.009 for trend-time analysis.
Year RR 95% CI 1 1.52 1.01-2.29 2 1.00 0.67-1.49 3 0.87 0.55-1.37 4+5 0.67 0.43-1.04 * a 70 60 50 40 30 20 Number of Second CHD Events 1 2 3 4+5 Year Placebo HRT
• Wyeth’s “physician awareness and use
study” found
“— Among physicians aware of HERS data, half (51%) recall benefits of HRT, particularly cardiovascular benefits (40%) as main
conclusion of the information, while one-quarter (25%) came away with negative impressions about cardiovascular risk associated with HRT...”
• Even for women at high risk for
cardiovascular disease, only a minority (13%) of physicians said they planned to decrease their prescribing of Prempro
• More than two-thirds (69%) said the
HERS study will have no impact on use of Prempro for women at high risk for cardiovascular disease.
Doubt is Our Product
Even physicians who understood that
HERS showed that hormone therapy
did not benefit women with heart
disease still believed that
hormone therapy could
benefit healthy women.
2002:
Estrogen-progestin arm of the WHI
halted because the treated group
experienced higher rates of breast
cancer, CVD, and overall harm
(WGWHI 2002)
The Women’s Health Initiative
2004:
Estrogen-only arm halted because
of increased stroke risk in the
treated group, and because estrogen
failed to show any cardiovascular
The Women’s Health Initiative
2004:
E/P is shown to double the risk of
VTE (Cushman 2004) and
The Fountain of Youth for
Men: Testicular Extracts
1889:
• Charles Édouard
Brown-Séquard, age 72, announced to the Société de Biologie
that he had reversed his
physical decline by injecting an extract of dog and guinea pig testicles
Surgical Rejuvenation
• Eugen Steinach, a Viennese surgeon,
was famous for his vasectomies
• Serge Voronoff, in Paris, transplanted
sliced ape testicles into human scrota • L.L. Stanley transplanted the testicles of
executed prisoners at San Quentin Penitentiary
Testosterone & Male Menopause
• 1935: Testosterone synthesized
• 1939: Male menopause diagnosed
• 1942: “The male climacteric presents
one of the complex problems of
aging. ..Its symptomology is uninvolved, tremendously varied, and rarely brought to the attention of the physician in all its diversity”
Provenance of the Low-T Quiz
• Developed by Dr. Morley for Organon BioSciences,
the Androgen Deficiency in Aging Males (ADAM) test was later rebranded as the ‘Is It Low T?’ Quiz
• “Dr. Morley recalls that he draJed the
quesLonnaire in 20 minutes in the bathroom,
scribbling the quesLons on toilet paper and giving them to his secretary the next day to type up.”
• “I have no trouble calling it a crappy
quesLonnaire,” he says.
Testosterone and CVD Risk
• The only placebo-controlled trial of
testosterone therapy that specifically examined cardiovascular disease and mortality endpoints, a study of 209 men over the age of 65 with low
testosterone, was stopped early because of an increased risk of cardiovascular events.
CVD Risks: Meta-Analysis
• A meta-analysis of 2,994 men in 27
trials identified 180 heart attacks and other cardiovascular-related event; testosterone therapy
significantly increased the risk of cardiovascular events (odds ratio 1.54).
• Trials funded by the pharmaceutical
industry found no increased risk, while studies not funded by the
pharmaceutical industry found that treatment doubled risk (OR 2.06).
Treatment of Men for “Low
Testosterone”: A Systematic Review
• Databases were searched between 1950
and 2013
• 217 randomized, placebo-controlled studies
of testosterone for cardiovascular benefit, sexual function, mood and behavior, or
cognition in men were identified
– studies involving body building or contraceptive
effectiveness were excluded
Testosterone and CVD
• Evidence supporting the use of testosterone for
preventing or treating cardiovascular disease is inconsistent and unconvincing.
• Studies are mixed on angina (2/4 showed no
effect)
• Three studies from the same group found a
benefit for symptoms associated with congestive heart failure.
• One study was stopped early for adverse
Testosterone & Sexual Function
• 23/41 studies that assessed sexual
function as a primary or secondary endpoint found no
testosterone-associated improvements in any sexual function end point.
• Sixteen studies reported beneficial
effects of testosterone treatment for at least one measure of sexual function or satisfaction; 2 studies were mixed.
Testosterone &
Erectile Dysfunction
• Two-thirds (20/32) of the studies that
evaluated erectile function or sexual function showed no improvement with testosterone
• 8/10 studies of men with erectile
dysfunction found no benefit of testosterone over placebo
• 11/21 studies that reported changes in
Testosterone, Muscle & Mood
• Testosterone supplementation
consistently increased muscle
strength but did not have beneficial effects on physical function.
• Most studies on mood-related end
points found no beneficial effect of testosterone treatment on
personality, psychological well-being, or mood.
Conclusions
• Estrogen and testosterone have both
been promoted as anti-aging therapies and as disease preventives.
• Both have been promoted for CVD
prevention.
• Both have been linked with an increase
in cardiovascular events and other serious adverse events
