Promoting the Fountain of Youth: Low-T and Estrogen Deficiency

Transcription

1 Promoting the Fountain of Youth: Low-T and Estrogen Deficiency Adriane Fugh-Berman MD Georgetown University Medical Center

2 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 were used

3 The Estrogen Era 1920s: Estrone (theelin) isolated from pregnant women 1928: Progynon (from human placenta) 1933: Progynova (estradiol) 1938: Ethinyl estradiol 1942: Premarin (conjugated equine estrogens)

4 1945

5 1947

6 1957

7 1957

8 1959 Difficult family situations can often be wholly remedied by estrogen therapy for the woman involved. Wilson, Feminine Forever, 1966

9 JAMA 1968;206(9):2150

10 JAMA July 1, 1968; 205(1):8

11 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.

12 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 temporary commitment...

13 1998

14 HERS: Second CHD Events Number of Second CHD Events Placebo HRT Year RR 95% CI * Year *P=.009 for trend-time analysis.

15 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 onequarter (25%) came away with negative impressions about cardiovascular risk associated with HRT...

16 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.

17 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.

18 The Women s Health Initiative 2002: Estrogen-progestin arm of the WHI halted because the treated group experienced higher rates of breast cancer, CVD, and overall harm (WGWHI 2002)

19 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 benefit

20 The Women s Health Initiative 2004: E/P is shown to double the risk of VTE (Cushman 2004) and dementia (Shumaker 2004)

21

22 The Fountain of Youth for Men: Testicular Extracts 1889: Charles Édouard BrownSéquard, 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

23 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

24

25

26 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 Hoberman, Testosterone Dreams, 2005

27 Condition Branding: Low-T

28 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. (Singer N, NYT 11/23/13)

29

30

31 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. (Basaria 2010)

32 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).

33 Treatment of Men for Low Testosterone : A Systematic Review Databases were searched between 1950 and 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 (Huo S, Scialli AR, McGarvey S, Hill E, Tügertimur B, Fugh-Berman A, in submission)

34 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 cardiovascular events.

35 Testosterone & Sexual Function 23/41 studies that assessed sexual function as a primary or secondary endpoint found no testosteroneassociated 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.

36 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 libido found no effect

37 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 wellbeing, or mood.

38 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 The Fountain of Youth remains elusive