Endnotes Chapters 16,17,18,19,20

Chapter 16
1 Only heart disease kills more people than cancer. E. Arias and B. L. Smith. 2003. “Deaths: preliminary data for 2001.” National Vital Statistics Reports 51(5), www.cdc.gov/nchs/data/nvsr/
nvsr51/nvsr51_05.pdf. and R. Davis. 2004. “Cancer stats cite new danger.” USA Today online edition, Jan 14. See www.usatoday.com/news/health/2004-01-15-cancer-obesity_x.htm.
2 Infection with Helicobacter pylori bacteria is one of the primary factors leading to stomach cancer. J. Parsonnet et al. 1994. “Helicobacter pylori infection and gastric lymphoma.” N Engl J Med. May 5;330(18): 1267–1271. Methods of storing food may also be a factor. See S. H. Landis et al. 1999. “Cancer statistics, 1999.” Ca-A Cancer J Clin. 49(1): 8–31.
“Several reasons may have led to this drop in stomach cancer rates, such as improved detection and treatment as well as improved dietary habits, such as eating more fruits, vegetables, and fiber. Many studies show that a diet rich in fruits and vegetables lowers the risk for many cancers. But if stomach cancer is not caught early before it has spread, the prognosis is poor and the disease may be fatal.” (Cleveland Clinic, “Helicobacter pylori and stomach cancer,” www.clevelandclinic.org/health/health-info/docs/1800/
1816.asp?index58107&src5news).
“Cigarette smoking is the most important risk factor for lung cancer, accounting for 68 to 78 percent of lung cancer deaths among females and 88 to 91 percent of lung cancer deaths among males.” CDC. 1990. Cigarette smoking–attributable mortality and years of potential life lost—United States, 1990. Morbidity and Mortality Weekly Report 42(33): 645–649, reported in CDC and NIH, Healthy People 2010, www.healthypeople.gov/document/html/volume1/03cancer.htm.
“Unexplained cancer-related health disparities remain among population subgroups. For example, Blacks and people with low socioeconomic status have the highest overall rates for both new cancers and deaths.” National Cancer Institute, 2001 Progress Report, http://progressreport.cancer.gov/highlights.asp?coid517.
3 American Cancer Society, Cancer Facts & Figures 2002, www.cancer.org/downloads/STT/
CancerFacts&Figures2002TM.pdf.
4 Genomic Health information page, at www.genomichealth.com/oncotype/faq/pat.aspx; Biospace, CCIS, “The National Surgical Adjuvant Breast and Bowel Project (NSABP) and Genomic Health,
Inc. Announce Positive Results from Large-Scale, Prospective Validation Study to Quantify Breast
Cancer Recurrence in Newly Diagnosed Patients,” www.biospace.com/ccis/news_story.cfm?
StoryID514550020&full51.
5 “10 emerging technologies that will change your world.” MIT Technology Review, February 2004; www.technologyreview.com/articles/print_version/emerging0204.asp; H. Brody. “Taming the terahertz.” MIT Technology Review, June 2003; www.technologyreview.com/articles/innovation40603.asp.
6 “Spotting cancer before it sickens.” Wired News, April 9, 2003; www.wired.com/news/
medtech/0,1286,58407,00.html.
7 Ibid. See also, T. Parker-Pope. “Ten major advances you’re likely to see in the coming year.” Wall Street Journal, January 26, 2004; Y. Yu et al. 2004. “Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins.” Nature Biotech. 22(Mar 01): 313–320.
8 See T. J. Key et al. 2004. “Diet, nutrition and the prevention of cancer.” Public Health Nutr. Feb;7(1A): 187–200.
Yet this view remains controversial. In 2003, the U.S. Preventive Services Task Force (USPSTF) concluded “that the evidence is insufficient to recommend for or against the use of supplements of vitamins A, C, or E; multivitamins with folic acid; or antioxidant combinations for the prevention of cancer or cardiovascular disease.” See www.ahrq.gov/clinic/3rduspstf/vitamins/vitaminsrr.htm.
9 Instead of preventing cancer, radiation from mammograms has been identified as the cause of 3,000–5,000 additional cases of breast cancer each year. See J. W. Gofman and E. O’Connor. 1999. Radiation from Medical Procedures in the Pathogenesis of Cancer and Ischemic Heart Disease: Dose-Response Studies with Physicians per 100,000 Population. San Francisco: CNR Books.
10 We say there is “often” value in early detection because many cases of malignancy are already metastasized by the time they can be detected and their early detection has little predictive value.
11 Take the case of prostate cancer, for example. “Available screening tests (for example prostate specific antigen) can detect early stage disease but there is no evidence that clinical outcomes are improved by early detection. The potential harms of screening 28 million men older than 50 years include unnecessary interventions for thousands of men without disease or with clinically insignificant cancer. The billions of dollars required for this effort could displace resources away from health care services of proved benefit.” S. H. Woolf. 1994. “Public health perspective: the health policy implications of screening for prostate cancer.” J Urol. Nov;152(5 Pt 2): 1685–1688.
12 L. A. Koutsky.2002. “A controlled trial of a human papilloma virus type 16 vaccine.” N Engl J Med. Nov 21;347(21): 1645–1651.
13 O. J. Finn. 2003. “Cancer vaccines: between the idea and the reality.” Nat Rev Immunol. Aug;3(8): 630–641; R. C. Kennedy and M. H. Shearer. 2003. “A role for antibodies in tumor immunity.” Int Rev Immunol. Mar–Apr;22(2): 141–172.
14 E. Jonietz. “DNA drugs.” MIT Technology Review, November 2002; www.technologyreview.com/
articles/innovation51102.asp?p51.
15 “In normal development, [the surface molecule] 5T4 is involved in helping cells move around in a regulated way” according to Peter Stern at Cancer Research UK. “In cancer, it’s not regulated—it’s out of control.” S. Bhattacharya. “Stem cell mobility linked to cancer’s spread.” NewScientist.com. October 24, 2003; www.newscientist.com/news/news.jsp?id5ns99994309.
16 Interleukin-12 is not normally produced by cancer cells. “Mount Sinai School of Medicine conducting clinical trials with gene therapy for colorectal cancer.” Bio.com, January 22, 2004; www.bio.com/newsfeatures/newsfeatures_research.jhtml?cid5129742418&page51.
17 J. K. Gohagan et al. 2000. “The prostate, lung, colorectal and ovarian (PLCO) cancer screening trial of the National Cancer Institute: history, organization, and status.” Control Clin Trials. Dec;21(6 Suppl): 251S–272S.
18 National Cancer Institute, “Screening and Testing for Cancer;” www.nci.nih.gov/cancerinfo/
screening.
19 For more information about the DR-70 test, see the AMDL, Inc. site; www.amdl.com/
Products/DR-70/index.html.
20 Stanford University Medical Center, Office of Communication & Public Affairs, “Stanford researchers weigh risks vs. benefits of self-referred body scanning.” July 29, 2003; http://mednews.
stanford.edu/news_releases_html/2003/julyrelease/scanning.htm. The news release refers to J. Illes et al. 2003. “Self-referred whole-body CT imaging: current implications for health care consumers.” Radiology. Aug;228(2): 346–351.
21 Quoted in G. Kolata. “Questions grow over usefulness of some routine cancer tests.” New York Times, December 30, 2001.
22 The only food that cancer cells can eat is sugar, which is another reason we emphasize avoiding simple sugars in the diet as well as high-glycemic-index foods that raise blood sugar levels quickly.
23 T. Boehm et al. 1997. “Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance.” Nature. 390: 404–407.
24 Angiogenesis Foundation, “Understanding Angiogenesis”. www.angio.org/understanding/
content_understanding.html.
25 National Cancer Institute, Clinical Trial Results: “Bevacizumab (Avastin(tm)) Improves Survival in Metastatic Colorectal Cancer”; www.cancer.gov/clinicaltrials/results/bevacizumab-and-colorectal-cancer0601. With these trials showing benefit in colon cancer, trials are now looking at Avastatin in the treatment of renal cell cancer, prostate cancer, non-Hodgkin’s lymphoma, and many others.
26 J. Perkel. 2002. “Telomeres as the key to cancer.” The Scientist. 16(11):38; www.the-scientist.com/yr2002/may/profile_020527.html.
27 J. Alam. 2003. “Apoptosis: target for novel drugs.” Trends in Biotechnology. 21(11): 479–483.
28 There are over 700 gene therapy treatments being tested worldwide. There have been a number of highly publicized setbacks for some of these trials in the U.S. and Europe. Shenzhen SiBiono Gene Technologies Co. has been criticized for commercially releasing Gendicine too early without sufficiently large human trials. J. Hepeng. “First gene-therapy medicine commercialized.” Business Weekly, December 9, 2003; www1.chinadaily.com.cn/en/doc/2003-12/09/content_289867.htm; “Cancer gene therapy is first to be approved.” NewScientist.com, November 28, 2003; www.newscientist.com/news/news.jsp?id5ns99994420.
29 S. Bhattacharya. “Deadly spread of cancer halted.” NewScientist.com, June 5, 2003; www.newscientist.
com/news/news.jsp?id5ns99993801.
30 Cancer Research UK press release. “Scientists overpower cancer’s drug defenses,” February 19, 2004; www.cancerresearchuk.org/news/pressreleases/cancer_drugdefences_19feb04.
31 S. Bhattacharya. “GM blood kills human cancer cells.” NewScientist.com, April 1, 2003; www.
newscientist.com/news/news.jsp?id5ns99993574.
32 See P. J. Pickhardt et al. 2003. “Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults.” N Engl J Med. Dec 4;349: 2191–2200; M. M. Morrin and J. T. LaMont. 2003. “Screening virtual colonoscopy—Ready for prime time?” N Engl J Med. Dec 4;349: 2261–2264.
33 P. B. Cotton et al. 2004. “Computed tomographic colonography (virtual colonoscopy): a multicenter comparison with standard colonoscopy for detection of colorectal neoplasia.” JAMA. Apr 14;291(14): 1713–1719.
34 P. Lichtenstein et al. 2002. “The Swedish Twin Registry: a unique resource for clinical, epidemiological and genetic studies.” J Intern Med. Sep;252(3): 184–205; N. L. Pedersen et al. 2002. “The Swedish Twin Registry in the third millennium.” Twin Res. 5(5): 427–432.
35 See, for example, J. D. Hayes and R. C. Strange. 2000. “Glutathione S-transferase polymorphisms and their biological consequences.” Pharmacology. Sep;61(3): 154–166.
36 See our Web site Fantastic-Voyage.net for further information on available genomics tests.
37 Up to 48 percent of the cases of stomach cancer may be due to the GSTM 1 null polymorphism combined with mutations of the IL-1B and NAT1 genes, as demonstrated by C. A. Gonzalez et al. 2002. “Genetic susceptibility and gastric cancer risk.” Int J Cancer. Jul 20;100(3): 249–260.
38 Women often refuse to have the test for a myriad of reasons, such as concern over insurance coverage for preexisting conditions. “Misuse of genetic information can have devastating consequences—job loss, social stigmatization, loss of health and life insurance or inability to obtain them—and all these must be guarded against whenever possible.” “Genetic testing for breast and ovarian cancer susceptibility.” DukeMed Magazine, Summer 2001; http://dukemednews.duke.edu/news/controversy.php?id51733. See also, A. Berchuck and M. G. Muto. 1996. “Status of testing for genetic predisposition to ovarian cancer.” SCO Issues Fall;16(3); www.sgo.org/publications/SGOIssues/fall96/Science.html.
39 T. Soucci. 2000. “The p53 tumor suppressor gene: from molecular biology to clinical investigation.” Ann NY Acad Sci. Jun;910: 121–137; discussion 137–139.
40 T. J. Key et al. 2004, op cit.
41 The National Cancer Institute defines a serving as any of the following: one medium-size fruit (such as apple, orange, banana, pear), 1/2 cup raw, cooked, canned or frozen fruits or vegetables, 3/4 cup (6 oz.) 100 percent fruit or vegetable juice, 1/2 cup cut-up fruit, 1/2 cup cooked or canned legumes (beans and peas), 1 cup raw, leafy vegetables (lettuce, spinach), or 1/4 cup dried fruit (raisins, apricots, mango). For more information, visit the National Cancer Institute’s 5 A Day program page: www.5aday.gov.
42 Behavior risk factors surveillance system CD-ROM (1984–1995, 1996, 1998) and public use data tape (2000), National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and prevention, 1997, 1999, 2000, 2001.
43 C. N. Holick et al. 2002. “Dietary carotenoids, serum beta-carotene, and retinol and risk of lung cancer in the alpha-tocopherol, beta-carotene cohort study.” Am J Epidemiol. Sep 15;156(6): 536–547.
44 C. La Vecchia et al. 2001. “Nutrition and health: epidemiology of diet, cancer and cardiovascular disease in Italy.” Nutr Metab Cardiovasc Dis. Aug;11(4 Suppl): 10–15.
45 A. Trichopoulou et al. 2003. “Adherence to a Mediterranean diet and survival in a Greek population.” N Engl J Med. Jun 26;348(26): 2599–2608.
46 S. Watanabe, S. Uesugi, and Y. Kikuchi. 2002. “Isoflavones for prevention of cancer, cardiovascular diseases, gynecological problems and possible immune potentiation.” Biomed Pharmacother. Aug;56(6): 302–312.
47 Y. C. Wang and U. Bachrach. 2002. “The specific anti-cancer activity of green tea (-)-epigallocatechin-3-gallate (EGCG).” Amino Acids. 22(2): 131–143.
48 V. Rice. “University Health Network researchers discover new class of human stem cells.” University of Toronto news release, June 8, 2003; www.eurekalert.org/pub_releases?2003-06/uot-uhn060503.php.
49 R. W. Owen et al. 2000. “Olive-oil consumption and health: the possible role of antioxidants.” Lancet Oncol. Oct;1: 107–112.
50 E. Giovannucci et al. 2002. “Importance of lycopene and tomato products to prevent prostate cancer. A prospective study of tomato products, lycopene, and prostate cancer risk.” J Natl Cancer Inst. Mar 6;94(5): 391–398.
51 O. Warburg. 1956. “On the origin of cancer cells.” Science. Feb 24;123(3191): 309–314.
52 S. Higgenbotham et al. 2004. “Dietary glycemic load and risk of colorectal cancer in the Women’s Health Study.” J Natl Cancer Inst. Feb 4;96(3): 229–233. Interestingly, the same researchers did not find a high-glycemic-load diet to be associated with an increased risk of breast cancer. S. Higgenbotham et al. 2004. “Dietary glycemic load and breast cancer risk in the Women’s Health Study.” Cancer Epidemiol Biomarkers Prev. Jan;13(1): 65–70.
53 D. S. Michaud et al. 2002. “Dietary sugar, glycemic load, and pancreatic cancer risk in a prospective study.” J Natl Cancer Inst. Sep 4;94(17): 1293–1300.
54 American Cancer Society. “Fitting in Fitness.” www.cancer.org/docroot/PED/content/
PED_6_1X_Be_Physically_Active_Achieve_and_Maintain_a_Healthy_Weight.asp?sitearea5PED.
55 Much of the concern over sunlight exposure seems misdirected. While excessive exposure to bright sunlight will damage skin and increase the incidence of skin cancer, moderate exposure to sunlight may be cancer protective, as shown in the study by W. B. Grant. 2002. “An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation.” Cancer. Mar 15;94(6): 1867–1875.
56 A. P. Albino et al. 2000. “Cell cycle arrest and apoptosis of melanoma cells by docosahexaneoic acid: association with decreased pRb phosphorylation.” Cancer Res. Aug 1;60(15): 4139–4145.
57 L. Settimi et al. 2001. “Cancer risk among male farmers: a multi-site case-control study.” Int J Occup Med Environ Health. 14(4): 339–347.
58 These results come from the 1999–2000 National Health and Nutrition Examination Survey (NHANES). The report, “Prevalence of Overweight and Obesity Among Adults: United States, 1999–2000,” is available at the CDC Web site www.cdc.gov/nchs/products/pubs/pubd/hestats/
obese/obse99.htm. See also K. M. Flegal et al. 2002. “Prevalence and trends in obesity among U.S. adults, 1999–2000.” JAMA. 288: 1723–1727.
59 E. E. Calle et al. 2003. “Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.” N Engl J Med. Apr 24;348(17): 1625–1638.
60 R. A. Freitas Jr. 2002. “The future of nanofabrication and molecular scale devices in nanomedicine.” Studies in Health Technology and Informatics. 80: 45–59.
61 X. H. Gao et al. 2002. “Quantum-dot nanocrystals for ultrasensitive biological labeling and multicolor optical encoding.” Journal of Biomedical Optics. 7(4): 532–537.
62 Fred Hutchinson Cancer Research Center press release. “Intel and Fred Hutchinson to explore the use of nanotechnology tools for early disease detection.” Fred Hutchinson Cancer Research Center. October 23, 2003; www.eurekalert.org/pub_releases/2003-10/fhcr-iaf102303.php.
63 “Optical biopsies on horizon using noninvasive biomedical imaging technique developed by Cornell-Harvard group.” Cornell News Service, June 11, 2003; www.news.cornell.edu/releases/
June03/Intrinsic.Fluor.hrs.html.
64 M. Kelly. “Startups seek perfect particles to search and destroy cancer.” Small Times, April 18, 2003; www.smalltimes.com/document_display.cfm?document_id55867.
65 Ibid.
66 J. Couzin. “Nanoparticles Cut Tumors’ Supply Lines,” Science, June 27, 2002; http://sciencenow.
sciencemag.org/cgi/content/full/2002/627/3.
67 E. Cameron and L. Pauling. 1992. Cancer and Vitamin C: A Discussion of the Nature, Causes, Prevention, and Treatment of Cancer with Special Reference to the Value of Vitamin C. Philadelphia: Camino Books.
68 Q. S. Zheng and R. L. Zheng. 2002. “Effects of ascorbic acid and sodium selenite on growth and redifferentiation in human hepatoma cells and its mechanisms.” Pharmazie. Apr;57(4): 265–269.
69 A. J. Duffield-Lillico et al. 2002. “Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial.” Cancer Epidemiol Biomarkers Prev. Jul;11(7): 630–639.
70 O. Portakal et al. 2000. “Coenzyme Q10 concentrations and antioxidant status in tissues of breast cancer patients.” Clin Biochem. Jun;33(4): 279–284.
71 S. P. Verma et al. 1997. “Curcumin and genistein, plant natural products, show synergistic inhibitory effects on the growth of human breast cancer MCF-7 cells induced by estrogenic pesticides.” Biochem Biphy Res Comm. 233: 692–696.
72 R. Rashmi, T. R. Santhosh Kumar, and D. Karunagaran. 2003. “Human colon cancer cells differ in their sensitivity to curcumin-induced apoptosis and heat shock protects them by inhibiting the release of apoptosis-inducting factor and caspases.” FEBS Lett. Mar 13;538(1-3): 19–24; T. Kawamori et al. 1999. “Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer.” Cancer Res. 59: 597–601.
73 R. A. Freitas Jr. “Robots in the bloodstream: the promise of nanomedicine.” KurzweilAI.net, February 26, 2002; www.kurzweilai.net/meme/frame.html?main5/articles/art0410.html.
74 R. Smith. “Lung cancer cluster bombs created by researchers.” Medical News Today, January 31, 2004; www.medicalnewstoday.com/index.php?newsid55604.
75 J. Mason. “Coatings and arrays help put medication where it’s needed.” Small Times, June 27, 2003; www.smalltimes.com/document_display.cfm?document_id56288.
76 J. Gorman. “Buckymedicine: Coming soon to a pharmacy near you?” Science News, July 13, 2002; www.sciencenews.org/20020713/bob10.asp.
77 D. Penman. “Carbon nanotubes show drug delivery promise.” NewScientist.com, December 16, 2003; www.newscientist.com/news/news.jsp?id5ns99994485.
78 M. R. McDevitt et al. 2001. “Tumor Therapy with Targeted Atomic Nanogenerators.” Science. Nov 16;294(5546): 1537–1540.
79 “Nanoprobe to be developed for a ‘Fantastic Voyage’ in the human body, finding and treating deadly tumors.” Today@UCI, May 8, 2003; http://today.uci.edu/news/release_detail.asp?key5995.
80 “Lasers operate inside single cells.” Nature Science Update, October 6, 2003; www.nature.com/
nsu/030929/030929-12.html.
81 “Microbeams have big impact on cancer cells.” Reuters, December 2, 2003; www.cnn.com/
2003/HEALTH/conditions/12/02/cancer.microbeams.reut/index.html.
82 A. Salkever. “How High Tech Is Operating on Medicine.” Business Week, October 15, 2002; www.businessweek.com/technology/content/oct2002/tc20021015_8842.htm.
83 R. A. Freitas Jr., op cit.
84 A. Panzer and M. Viljoen. 1997. “The validity of melatonin as an oncostatic agent.” J Pineal Res. May;22(4):184–202.
85 S. Cos and E. J. Sanchez-Barcelo. 2000. “Melatonin, experimental basis for a possible application in breast cancer prevention and treatment.” Histol Histopathol. Apr;15(2): 637–647.
86 M. Eichholzer et al. 2001. “Folate and the risk of colorectal, breast and cervix cancer: the epidemiological evidence.” Swiss Med Wkly. Sep 22;131(37–38): 539–549.
87 H. Tapiero et al. 2002. “Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies.” Biomed Pharmacother. Jul;56(5): 215–222.
88 J. Virtamo et al. 2003. “Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up.” JAMA. Jul 23;290(4): 476–485.
89 M. Caraballoso et al. 2003. “Drugs for preventing lung cancer in healthy people.” Cochrane Database Syst Rev. (2):CD002141; A. Arora, C. A. Willhite, and D. C. Liebler. 2001. “Interactions of beta-carotene and cigarette smoke in human bronchial epithelial cells.” Carcinogenesis. Aug;22(8): 1173–1178.

Chapter 17
1 You can also use the “Life Expectancy Calculator” I used to calculate how long you might expect to live. It may be found at http://gosset.wharton.upenn.edu/~foster/mortality/perl/CalcForm.html.
2 Anne Collins’s Web site, “Ideal weight for men,” www.annecollins.com/weight-loss/ideal-weight-men.htm.
3 See Fantastic-Voyage.net.
4 The Ray & Terry Meal Replacement Shake is available at www.RayandTerry.com.

Chapter 18
1 See www.lloydwatts.com and the site of his company www.audience-inc.com. The tagline on the audience site is “We let machines hear.”
2 The University of Texas cerebellum simulation included 10,000 granule cells, 900 Golgi cells, 500 mossy fiber cells, 20 Purkinje cells, and 6 nucleus cells.
J. L. Raymond et al. 1996. “The cerebellum: a neuronal learning machine?” Science. 272: 1126–1131; J. J. Kim and R. F. Thompson. 1997. “Cerebellar circuits and synaptic mechanisms involved in classical eyeblink conditioning.” Trends Neuroscience. 20: 188–191; J. F. Medina et al. 2000. “Timing mechanisms in the cerebellum: testing predictions of a large-scale computer simulation.” Journal Neuroscience. 20: 5516–5525; D. V. Buonomano and M. D. Mauk. 1994. “Neural network model of the cerebellum: temporal discrimination and the timing of motor responses.” Neural Computation. 6: 38–55.
3 B. Fischl. 2000. “Measuring the thickness of the human cerebral cortex from magnetic resonance images.” Proc Natl Acad Sci USA. Sep 26;97(20): 11050–11055.
4 G. Huang. “Mind-machine merger.” MIT Technology Review, May 2003; www.technologyreview.com/
articles/print_version/huang0503.asp.
5 Ibid. In 2004, a research team plans to have a monkey in St. Louis control a robot in Ann Arbor as it moves through an obstacle course. The monkey will watch the robot’s movements on a screen, and the monkey’s commands and feedback from the robot will be sent via the Internet. This is an early step toward remote human control of robots by thought alone. See K. Philipkoski. “Transforming thoughts into deeds.” Wired News, January 14, 2004; www.wired.com/news/medtech/0,1286,61889,00.html; Reuters. “Monkey thinks, makes his moves.” Wired News, October 13, 2003; www.wired.com/news/medtech/
0,1286,60803,00.html.
6 The BrainBrowser Internet software is under development at Georgia State University. “When a user focuses his attention on a button, it becomes highlighted, and when the user successfully focuses on clicking the button, it emits a low tone.” “Browser boosts brain interface.” MIT Technology Review, May 22, 2003; www.technologyreview.com/articles/rnb_052203.asp?p51; see also R. Brooks. “Toward a brain-Internet link.” MIT Technology Review, November 2003; www.technology.review.com/articles/print_version/brooks1103.asp.
7 “Microchip promises smart artificial arms.” BBC News, June 15, 2003; http://news.bbc.co.uk/2/hi/health/2975828.stm.
8 J. Hogan. “Synapse chip taps into brain chemistry.” NewScientist.com, March 24, 2003; www.
newscientist.com/news/news.jsp?id5ns99993523.
9 D. H. Hubel and T. N. Wiesel. 1965. “Binocular interaction in striate cortex of kittens reared with artificial squint.” Journal of Neurophysiology. 28(6): 1041–1059.
10 M. A. Packer et al. 2003. “Nitric oxide negatively regulates mammalian adult neurogenesis.” Proc Natl Acad Sci USA. Aug 5;100(16): 9566–9571.
11 C. Lie Dieter et al. “Neurogenesis in the Adult Brain: New Strategies for CNS Diseases.” In Annual Reviews of Pharmacology and Toxicology (in press).
12 “Bat spit drug aids stroke victims.” BBC News, February 6, 2004; http://news.bbc.co.uk/go/pr/fr/-/1/hi/health/3465419.stm.
13 L. Spinney. 2004. “Tea strainer in the neck ‘stops strokes.’” New Scientist. 181(2432): 12.
14 “Neurologists create a font of human nerve cells.” Science Daily, adapted from a University of Rochester news release, February 16, 2004; www.sciencedaily.com/print.php?url5/
releases/2004/02/040216083710.htm.
15 S. Westphal. “Re-implanted stem cells tackle Parkinson’s.” NewScientist.com, April 8, 2002; www.newscientist.com/news/news.jsp?id5ns99992139.
16 G. Stix. 2003. “Ultimate self-improvement.” Sci Amer. Sept: 44.
17 E. Jonietz. “7 hot projects.” MIT Technology Review, December–January 2004; www.techologyreview.
com/articles/print_version/jonietz1203.asp.
18 “Key advance reported in regenerating nerve fibers.” Science Daily, based on news release from Children’s Hospital Boston, February 18, 2004; www.sciencedaily.com/print.php?url-/
releases/2004/02/040218075713.htm; D. Fischer, Z. He, and L. I. Benowtiz. 2004. “Counteracting the Nogo receptor enhances optic nerve regeneration if retinal ganglion cells are in an active growth state.” J Neurosci. Feb 18;24(7): 1646–1651. See also, S. Seethaler. 2004. “Scientists discover new gene essential for the development of normal brain connections resulting from sensory input.” UCSD news release; http://ucsdnews.ucsd.edu/newsreel/science/screst.asp.
19 R. Dotinga. “Cool new ways to save brains.” Wired News, Feb. 10, 2004; www.wired.com/
news/medtech/0,1286,62224,00.html.
20 One fRMI research group claims to be able to use fMRI to catch “a word or concept as it forms itself in the brain.” Marcel Just at Carnegie Mellon University has run tests on volunteers using a small number of concepts. “We have 12 categories and can determine which of the 12 the subjects are thinking of with 80 to 90 percent accuracy.” P. Ross. 2003. “Mind readers.” Sci Amer. Sept: 77.
21 fMRI image of Ray Kurzweil’s brain is courtesy of Inc. Magazine, “Your Brain on Innovation,” by T. Singer, September 2002.
22 Buddhist monks have also shown changes in brain activity when they were asked to “induce a state of compassion in themselves.” C. Newton. “Meditation and the brain.” MIT Technology Review, February 2004; www.technologyreview.com/articles/print_version/newton0204.asp; T. Singer. “The Innovation Factor: Your Brain on Innovation.” Inc. Magazine, September 2002.
23 R. E. Callaway and R. Yuste. (The Salk Institute for Biological Studies, Systems Neurobiology Laboratory). 2002. “Stimulating Neurons with Light,” Curr. Opin. Neurobiology. October 1; 12(5): 587.
24 B. L. Sabatini and K. Svoboda. 2000. “Analysis of calcium channels in single spines using optical fluctuation analysis.” Nature. 408: 589–593.
25 J. L. Etnier and D. M. Landers. 1995. “Brain Function and Exercise: Current Perspectives.” Sports Medicine. 19(2): 81–85.
26 “Direct brain-to-brain communication and the transfer of minds between bodies are among the advances forecast in a recent report by the U.S. National Science Foundation and Department of Commerce.” G. Brumfiel. 2002. “Futurists predict body swaps for planet hops.” Nature. Jul 25;418: 359.
Deep brain stimulation, by which electric current from implanted electrodes influences brain function, is one possible neural implant. See A. Abbott. 2002. “Brain implants show promise against obsessive disorder.” Nature. Oct 17;419: 658; B. Nuttin et al. 1999. “Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder.” Lancet. Oct 30;354(9189): 1526.
27 R. S. Hong et al. 2003. “Dynamic range enhancement for cochlear implants.” Otol Neurotol. Jul;24(4): 590–595; R. S. Tyler et al. 2002. “Three-month results with bilateral cochlear implants.” Ear Hear. Feb;23(1 Suppl): 80S–89S.
28 See the Retinal Implant Project Web site (www.rle.mit.edu/retinaweb/), which contains a range of resources including recent papers. Here is one such recent paper from the team: R. J. Jensen et al. 2003. “Thresholds for activation of rabbit retinal ganglion cells with an ultrafine, extracellular microelectrode.” Invest Ophthalmal Vis Sci. Aug;44(8): 3533–3543.
29 The FDA approved the Medtronic implant for this purpose in 1997 for only one side of the brain; it was approved for both sides of the brain on January 14, 2002. S. Snider. “FDA approves expanded use of brain implant for Parkinson’s disease.” U.S. Food and Drug Administration FDA Talk Paper, January 14, 2002; www.fda.gov/bbs/topics/ANSWERS/2002/ANS01130.html.
30 Medtronic also makes an implant for cerebral palsy. See S. Hart. “Brain implant quells tremors.” ABCNews.com, December 23, 1997; http:more.abcnews.go.com/sections/living/brainstim1223. Also see the Medtronic site, www.medtronic.com.
31 This prosthesis, already 10 years in development, would perform the short-term memory tasks of the hippocampus rather than simply stimulating brain activity. To develop it, the developers had to “devise a mathematical model of how the hippocampus performs under all possible conditions, build that model into a silicon chip, and then interface the chip with the brain.” D. Graham-Rowe. 2003. “The world’s first brain prosthesis revealed.” NewScientist.com 177(2386): 4; www.newscientist.com/news/news.jsp?id5ns99993488.
32 G. Zeck and P. Fromherz. 2001. “Noninvasive neuroelectronic interfacing with synaptically connected snail neurons immobilized on a semiconductor chip.” Proc Natl Acad Sci USA. Aug 28;98(18): 10457–10462.
33 Quantum dots are nanosize crystals based on photosensitive semiconductor materials that detect photons or fluoresce (light up) in specific colors based on their size. See R. C. Johnson. “Scientists activate neurons with quantum dots.” EE Times, December 6, 2001; www.eetimes.com/story/OEG20011204S0068.
34 M. George. 2003. “Stimulating the brain.” Sci Amer. Sept: 67–73; F. M. Mottagy et al. 1999. “Facilitation of picture naming after repetitive transcranial magnetic stimulation.” Neurology. 53: 1806–1812.
35 S. Pridmore et al. 2000. “Comparison of unlimited numbers of rapid transcranial magnetic stimulation (rTMS) and ECT treatment sessions in major depressive episode.” Int J Neuropsychopharmacol. Jun; 3(2): 129–134; www.wireheading.com/rtms/.
36 E. Stockstad. 2001. “New hints into the biological basis of autism.” Science. 294: 34–37.
37 D. J. Gerber et al. 2003. “Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit.” PNAS. 100: 8993–8998.
38 J. S. Rhodes et al. 2003. “Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running.” Behav Neurosci. Oct;117(5): 1006–1016.
39 B. Draganski et al. 2004. “Neuroplasticity: Changes in grey matter induced by training.” Nature. Jan;427: 311–312.
40 D. F. Hultsch et al. 1999. “Use it or lose it: engaged lifestyle as a buffer of cognitive decline in aging?” Psychol Agin. Jun;14(2): 245–263.
41 E. P. Noble. 2000. “Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: a review.” Eur Psychiatry. Mar; 15(2): 79–89.
42 F. H. Gage. 2003. “Brain: Repair yourself.” Sci Amer. Sept: 46–53.
43 M. A. McDaneil. 2003. “‘Brain-specific nutrients: a memory cure?” Nutrition. Nov–Dec; (11–12): 957–75.
44 J. Polich. 2001. “Cognitive effects of a ginkgo biloba/vinpocetine compound in normal adults: systematic assessment of perception, attention and memory.” Hum Psychopharmacol. Jul;16(5): 409–416.
45 P. Bönöczk et al. 2000. “Role of sodium channel inhibition in neuroprotection: effect of vinpocetine.” Brain Res. Bull. 53(3): 245–254; S. A. Erdo et al. 1996. “Vincamine and vincanol are potent blockers of voltage-gated Na channels.” Eur J Pharmacol. Oct 24;314(1–2): 69–73; R. Balestreri, L. Fontana, and F. Astengo. 1987. “A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction.” J Am Geriatr Soc. May;35(5): 425–430.
46 M. Furushiro et al. 1997. “Effects of administration of soybean lecithin transphosphatidylated phosphatidylserine on impaired learning of passive avoidance in mice.” Jpn J Pharmacol. Dec;75(4): 447–450.
47 E. H. Sharman et al. 2002. “Reversal of biochemical and behavioral parameters of brain aging by melatonin and acetyl L-carnitine.” Brain Res. Dec 13;957(2): 223–230.
48 “Researchers at the UCLA Neuropsychiatric Institute found significant improvement in verbal recall among a group of people with age-associated memory impairment who took the herbal supplement ginkgo biloba for six months when compared with a group that received a placebo.” R. Champeau. “UCLA researchers find ginkgo biloba may help improve memory.” UCLA news release, November 10, 2003; www.eurekalert.org/pub_releases/2003-11/uoc--urf111003.php. See also, R. W. Stackman et al. 2003. “Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimer’s disease by chronic ginkgo biloba treatment.” Exp Neurol. Nov;184(1): 510–520.
49 J. M. Bourre et al. 1991. “Essentiality of n-3 fatty acids for brain structure and function.” World Rev Nutr Diet. 66: 103–117.
50 D. S. Heron et al. 1980. “Lipid fluidity markedly modulates the binding of serotonin to mouse brain membranes.” Proc Natl Acad Sci. 77: 7463–7467.
51 A. P. Simopoulos. 2001. “Evolutionary aspects of diet and essential fatty acids.” World Rev Nutr Diet. 88: 18–27; A. P. Simopoulos, A. Leaf, and N. Salem. 1999. “Workshop on the essentiality of and recommended dietary intakes for omega-6 and omega-3 fatty acids.” J Am Coll Nutr. 18: 487–489.
52 There is not universal agreement about the optimal ratio of omega-6 to omega-3 fatty acid consumption. Dr. Yehuda et al. from Israel feels that a 4:1 ratio is optimal. See S. Yehuda et al. 2002. “The role of polyunsaturated fatty acids in restoring the aging neuronal membrane.” Neurobiol Aging. Sep–Oct;23(5): 843–853.
53 E. Nemets et al. 2002. “Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder.” Am J Psychiatry. 159: 477–479; L. B. Marangell et al. 2003. “A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaneoic acid in the treatment of major depression.” Am J Psychiatry. 160: 996–998.
54 S. Y. Chung et al. 1995. “Administration of phosphatidylcholine increases brain acetylcholine concentration and improves memory in dementia mice.” J Nutr. Jun;125(6): 1484–1489.
55 S. L. Ladd et al. 1993. “Effect of phosphatidylcholine on explicit memory.” Clin Neuropharmacol. Dec;16(6): 540–549.
56 “Memory is a biological process that can be manipulated by modern biology like anything else. Not only can you disrupt it, you can improve it,” according to Timothy Tully of Helicon Therapeutics. Another founder of memory research, Nobel laureate Eric Kandel, has explored memory using a marine snail model. Some of the nerve cells in the Aplysia slug are “big enough to be seen with the naked eye.” R. Langreth. “Viagra for the brain.” Forbes.com, February 4, 2002; www.forbes.com/forbes/2002/0202/046_print.html.
57 F. Fagnani et al. 2004. “Donepezil for the treatment of mild to moderate Alzheimer’s disease in France: the economic implications.” Dement Geriatr Cogn Disord. 17(1–2): 5–13; K. R. Krishnan et al. 2003. “Randomized, placebo-controlled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer’s disease.” Am J Psychiatry. Nov;160(11): 2003–2011.

Chapter 19
1 N. Carvalhaes-Neto et al. 2002. “Urinary free cortisol is similar in older and younger women.” Exp Aging Res. Apr–Jun;28(2): 163–168; E. Beale et al. 2002. “Changes in serum cortisol with age in critically ill patients.” Gerontology. Mar–Apr;48(2): 84–92.
2 R. Sapolsky. 1998. Why Zebras Don’t Get Ulcers. New York: W. H. Freeman.
3 D. S. Khalsa and C. Stauth. 1997. Brain Longevity. New York: Warner Books.
4 E. Ferrari et al. 2001. “Age-related changes of the adrenal secretory pattern: possible role in pathological brain aging.” Brain Res Rev. Nov;37(1–3): 294–300; E. Ferrari et al. 2001. “Age-related changes of the hypothalamic-pituitary-adrenal axis: pathophysiological correlates.” Eur J Endocrinol. Apr;144(4): 319–329.
5 For information on this test, see Fantastic-Voyage.net.
6 According to one study, “The physiological role of dehydroepiandrosterone (DHEA) and its sulphated ester DHEA(S) has been studied for nearly 2 decades and still eludes final clarification.” The authors also suggest that the availability of the supplement is “hampering the rigorous scientific evaluation of its potential.” M. Racchi, C. Balduzzi, and E. Corsini. 2003. “Dehydroepiandrosterone (DHEA) and the aging brain: flipping a coin in the ‘fountain of youth.’” CNS Drug Rev Spring;9(1): 21–40. See also M. Boudarene and J. J. Legros. 2002. “Study of the stress response: role of anxiety, cortisol and DHEAs.” Encephale. Mar–Apr;28(2): 139–146.
7 S. Shibata. 2000. “A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice.” Yakugaku Zasshi. Oct;120(10): 849–862.
8 B. Singh et al. 2001. “Adaptogenic activity of a novel, withanolide-free aqueous fraction from the roots of Withania somnifera Dun.” Phytother Res. Jun;15(4): 311–318.
9 Barry Sears has long been preaching the gospel of the hazards of cortisol and insulin. See The Anti-Aging Zone. New York: HarperCollins, 1999, p. 138.
10 www.sciam.com/article.cfm?chanID5sa003&articleID5000C601F-8711-1F99-86FB83414B7F0156.
11 P. Zimmet and S. Baba. 1990. “Central obesity, glucose intolerance and other cardiovascular disease risk factors: an old syndrome rediscovered.” Diabetes Res Clin Pract. 10(Suppl 1): S167–171.
12 J. Nandi et al. 2002. “Central mechanisms involved with catabolism.” Curr Opin Clin Nutr Metab Care. Jul;5(4): 407–418.
13 According to one study, “Insulin resistance is an important risk factor for type 2 diabetes and coronary heart disease. Our results suggest that genetic factors, intrauterine environment, early childhood, and adult environmental factors are all relevant in determining adult insulin resistance.” D. A. Lawlor, G. Smith, and S. Ebrahim. 2003. “Life course influences on insulin resistance: findings from the British Women’s Heart and Health Study.” Diabetes Care. Jan;26(1): 97–103.
See also, J. P. Despres et al. 1996. “Hyperinsulinemia as an independent risk factor for ischemic heart disease.” N Engl J Med. Apr 11;334(15): 952–957.
14 W. Regelson and C. Colman. 1996. The Super Hormone Promise. New York: Simon and Schuster.
15 W. Leowattana. 2001. “DHEA(S): the fountain of youth.” J Med Assoc Thai. Oct;84(Suppl 2): S605–612.
16 J. A. Lemon, D. R. Boreham, and C. D. Rollo. 2003. “A dietary supplement abolishes age-related cognitive decline in transgenic mice expressing elevated free radical processes.” Exp Biol Med. 228: 800–810; R. N. Butler et al. 2002. “Is there an anti-aging medicine?” Journals of Gerontology Series A: Biol Sci Med Sci 57: B333–B338.
17 E. Barrett-Connor, K. T. Khaw, and S. S. Yen. 1986. “A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease.” N Engl J Med. Dec 11;315(24): 1519–1524.
18 R. H. Straub et al. 2002. “Dehydroepiandrosterone in relation to other adrenal hormones during an acute inflammatory stressful disease state compared with chronic inflammatory disease: role of interleukin-6 and tumour necrosis factor.” Eur J Endocrinol. Mar;146(3): 365–374.
19 W. Regelson. 1985. “Vitamin A, dehydroepiandrosterone (DHEA) and 5' nucleotidase: regulatory factors in tumor growth.” Cancer Invest. 3(4): 407–409.
20 A. H. Young, P. Gallagher, and R. J. Porter. 2002. “Elevation of the cortisol-dehydroepiandrosterone ratio in drug-free depressed patients.” Am J Psychiatry. Jul;159(7): 1237–1239.
21 According to one study, “Increases in mental and physical sexual arousal ratings significantly increased in response to an acute dose of DHEA in postmenopausal women.” L. Hackbert and J. R. Heiman. 2002. “Acute dehydroepiandrosterone (DHEA) effects on sexual arousal in postmenopausal women.” J Women’s Health Gend Based Med. Mar;11(2): 155–162.
See also R. F. Spark. 2002. “Dehydroepiandrosterone: a springboard hormone for female sexuality.” Fertil Steril. Apr;77(Suppl 4): 19–25.
22 W. Leowattana, op cit.
23 D. Rudman et al. 1990. “Effects of human growth hormone in men over 60 years old.” N Engl J Med. Jul 5;323(1): 1–6.
24 At www.ncbi.nlm.nih.gov, search the PubMed database for “growth hormone” to see these results.
25 A. Vermeulin. 2002. “Aging, hormones, body composition, metabolic effects.” World J Urol. May;20(1): 23–27.
26 R. D. Murray et al. 2002. “Low-dose GH replacement improves the adverse lipid profile associated with the adult GH deficiency syndrome.” Clin Endocrinol (Oxf). Apr;56(4): 525–532.
27 A. M. Ahmad et al. 2002. “Effects of GH replacement on 24-h ambulatory blood pressure and its circadian rhythm in adult GH deficiency.” Clin Endocrinol (Oxf). Apr;56(4): 431–437.
28 J. Svensson et al. 2002. “Effects of seven years of GH-replacement therapy on insulin sensitivity in GH-deficient adults.” J Clin Endocrinol Metab. May;87(5): 2121–2127.
29 D. E. Cummings and G. R. Merriam. 1999. “Age-related changes in growth hormone secretion: should the somatopause be treated?” Semin Reprod Endocrinol. 17(4): 311–325.
Research is also being conducted on GH treatment in adults worldwide. See, for example, Y. B. Sverrisdottir et al. 2003. “The effect of growth hormone (GH) replacement therapy on sympathetic nerve hyperactivity in hypopituitary adults: a double-blind, placebo-controlled, crossover, short-term trial followed by long-term open GH replacement in hypopituitary adults.” J Hypertens. Oct;21(10): 1905–1914.
30 Other points to consider: this study utilized the “high-dose low-frequency” GH injection protocol. Most anti-aging physicians recommend “low-dose high-frequency” GH therapy to reduce side effects. Also, artificial, not bio-identical forms of estrogen, progestin, and testosterone were used. See M. R. Blackman et al. 2002. “Growth hormone and sex steroid administration in healthy aged women and men.” JAMA. 288: 2282–2292.
31 M. Shim and P. Cohen. 1999. “IGFs and human cancer: implications regarding the risk of growth hormone therapy.” Horm Res. 51(Suppl 3): 42–51.
32 A. Beentjes et al. 2000. “One year growth hormone replacement therapy does not alter colonic epithelial cell proliferation in growth hormone deficient adults.” Clin Endocrinol (Oxf). Apr;52(4): 457–462 and M. Letsch et al. 2003. “Growth hormone-releasing hormone (GHRH) antagonists inhibit the proliferation of androgen-dependent and -independent prostate cancers.” Proc Natl Acad Sci USA. Feb 4;100(3): 1250–1255; M. H. Torosian. 1993. “Growth hormone and prostate cancer growth and metastasis in tumor-bearing animals.” J Pediatr Endocrinol. Jan–Mar;6(1): 93–97.
33 J. R. Stout. 2002. “Amino acids and growth hormone manipulation.” Nutrition. July–Aug;18(7–8): 683–684; R. Savine and P. H. Sonksen. 1999. “Is the somatopause an indication for growth hormone replacement?” J Endocrinol Invest. 22(5 Suppl): 142–149.
34 A. J. Morales et al. 1998. “The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women.” Clin Endocrinol (Oxf). Oct;49(4): 421–432.
35 D. Leger et al. 2004. “Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy.” Am J Med. Jan 15;116: 91–95.
36 Studies of women who work night shifts have been used to explore the role of melatonin. The implications of the results, which showed an increase in risk, “‘extend beyond women who work at night’ . . . ‘Women in developing countries have one-fifth the risk of breast cancer compared to women in industrialized nations’ . . . It is possible that exposure to more light at night, a common phenomenon in industrialized nations, may account for increased cancer risk in women. ‘This has implications that are independent of shift work.’” M. T. Willis. 2001. “Light at night,” ABCNews.com (abcnews.go.com/sections/
living/DailyNews/breastcancer011016.html). See E. Schernhammer et al. 2003. “Night-shift work and risk of colorectal cancer in the Nurses’ Health Study.” JNCI. Jun 4:95(11): 825–828.
See also Y. Touitou. 2001. “Human aging and melatonin. Clinical relevance.” Exp Gerontol. Jul;36(7): 1083–1100; F. Fraschini et al. 1998. “Melatonin involvement in immunity and cancer.” Biol Signals. Jan;7(1): 61–72.

Chapter 20
1 It is interesting that in the rush to “level the playing field” in the name of sexual equality, many physicians seem to have lost sight of the fact that there are, nevertheless, major physical differences between men and women. Recent research suggests that gender must be taken into account when many types of drugs and other therapies are used. There are significant differences between men and women in the function of their brains, hearts, lungs, and immune and digestive systems, in addition to their obvious differences in reproductive systems. For more information, see M. J. Legato. 2002. Eve’s Rib: The New Science of Gender-Specific Medicine and How It Can Save Your Life. New York: Harmony Books.
2 BERT isn’t really new, but has been around for decades. It is now becoming more widely known, thanks to popular books such as Suzanne Somers’s The Sexy Years. 2004. New York: Crown.
3 Interestingly, the makers of Premarin seem proud of this fact and promote Premarin as containing “estrogens obtained exclusively from natural sources,” even though these natural sources are pregnant mare urine.
4 V. W. Pinn et al. 2002. NIH Research and Other Efforts Related to the Menopausal Transition. April 22. Bethesda, Maryland: Office of Research on Women’s Health/National Institutes of Health (www4.od.nih.gov/orwh/MenopauseRpt4-02.pdf).
5 A. Vashisht et al. 2001. “Prevalence of and satisfaction with complementary therapies and hormone replacement therapy in a specialist menopause clinic.” Climacteric. Sep;4(3): 250–256. See also S. L. Nand et al. 1998. “Menopausal symptom control and side-effects on continuous estrone sulfate and three doses of medroxyprogesterone acetate. Ogen/Provera Study Group.” Climacteric. Sep;1(3): 211–218.
6 The lack of consensus is not due to lack of effort. Several trials are currently under way or have recently concluded, which attempt to provide better guidance for menopausal women. The main studies include the Women’s Health Initiative (WHI), the Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial, the Heart and Estrogen-Progestin Replacement Study (HERS), the Women’s International Study of long Duration Oestrogen after Menopause (WISDOM), and the Million Women Study.
7 For an interesting discussion of the types of problems faced by today’s clinicians in deciding what types of women and what risk factors are amenable to HRT, see J. E. Manson and K. A. Martin. 2001. “Clinical practice. Postmenopausal hormone-replacement therapy.” N Engl J Med. Jul 5;345(1): 34–40.
8 J. A. Cauley et al. 2001. “Effects of hormone replacement therapy on clinical fractures and height loss: The Heart and Estrogen/Progestin Replacement Study (HERS).” Am J Med. Apr 15;110(6): 442–450.
9 M. P. Warren et al. 2003. “Persistent osteopenia in ballet dancers with amenorrhea and delayed menarche despite hormone therapy: A longitudinal study.” Fertil Steril. Aug;80: 398–404.
10 J. A. Cauley et al. 2003. “Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial.” JAMA. Oct 1;290(13): 1729–1738.
11 C. T. Owens. 2002. “Estrogen replacement therapy for Alzheimer disease in postmenopausal women.” Ann Pharmacother. Jul;36(7): 1273–1276 and K. Yaffe. 1998. “Estrogen therapy in postmenopausal women: effects on cognitive function and dementia.” JAMA. Mar 4;279(9): 688–695.
12 Conclusions from the large Heart and Estrogen/Progestin Replacement Study suggest that women at risk of heart disease suffer an even greater cardiac risk by taking HRT. For low-risk women, “There is a risk that women without coronary heart disease might experience even greater net harm from HRT.” See J. A. Blakely. 2000. “The heart and estrogen/progestin replacement study revisited: hormone replacement therapy produced net harm, consistent with the observational data.” Arch Intern Med. Oct 23;160(19): 2897–2900. Also see R. SoRelle. 2002. “Second year of HERS same as the first—no clear benefit or harm for cardiovascular disease.” Circulation. Feb 26;105(8): e9077–9078; T. W. Meade and M. R. Vickers. 1999. “HRT and cardiovascular disease.” J Epidemiol Biostat. 4(3): 165–190.
13 G. A. Colditz et al. 1995.” The use of estrogens and progestins and the risk of breast cancer in postmenopausal women.” N Engl J Med. Jun 15;332(24): 1589–1593.
14 C. Rodriguez et al. 1995. “Estrogen replacement therapy and fatal ovarian cancer.” Am J Epidemiol. May 1;141(9): 828–835.
15 Writing Group for the Women’s Health Initiative Investigators. 2002. “Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.” JAMA. 288: 321–333.
16 Data taken from the American College Of OB/GYN Web site (“Questions and Answers on Hormone Therapy,” www.acog.org/from_home/publications/press_releases/nr08-30-02.cfm). All the data were not bad for women who took Prempro, however. A 37 percent decrease in colon cancer and a 24–34 percent decrease in bone fractures were seen as well.
17 A. L. Hersh, M. L. Stefanick, and R. S. Stafford. 2004. “National use of postmenopausal hormone therapy: annual trends and response to recent evidence.” JAMA. Jan 7; 291(1): 47–53; J. S. Haas et al. 2004.” Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results.” Ann Intern Med. Feb 3;140(3): 184–188.
18 J. T. Hargrove et al. 1989. “Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone.” Obstet Gynecol. Apr;73(4): 606–612.
19 A. DuPont et al. 1991. “Comparative endocrinological and clinical effects of percutaneous estradiol and oral conjugated estrogens as replacement therapy in menopausal women.” Maturitas. Oct;13(4): 297–311.
20 K. M. Prestwood et al. 2000. “The effect of low dose micronized 17ss-estradiol on bone turnover, sex hormone levels, and side effects in older women: a randomized, double-blind, placebo-controlled study.” J Clin Endocrinol Metab. Dec;85(12): 4462–4469. See also B. Ettinger et al. 1992. “Low-dosage micronized 17 beta-estradiol prevents bone loss in postmenopausal women.” Am J Obstet Gynecol. Feb;166(2): 479–88.
21 M. C. Snabes et al. 1997. “Physiologic estradiol replacement therapy and cardiac structure and function in normal postmenopausal women: A randomized, double-blind, placebo-controlled crossover trial.” Obstet Gynecol. 89: 332–339; G. M. C. Rosano et al. 1993. “Beneficial effect of oestrogen on exercise induced myocardial ischemia in women with coronary artery disease.” Lancet. 342: 133–136; C. Haines et al. 1996. “Effect of oral estradiol on Lp(a) and other lipoproteins in postmenopausal women. A randomized, double-blind, placebo-controlled crossover study.” Arch Intern Med. 156: 886–872.
22 H. N. Hodis et al. 2003. “Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women.” N Engl J Med. Aug 7;349(6): 535–545.
23 A. Kamada et al. 2004. “A new series of estrogen receptor modulators: effect of alkyl substituents on receptor-binding affinity.” Chem Pharm Bull (Tokyo). Jan;52: 79–88.
24 D. Yin et al. 2003. “Pharmacodynamics of selective androgen receptor modulators.” J Pharmacol Exp Ther. Mar;304(3): 1334–1340.
25 E. N. Meilahn et al. 1998. “Do urinary oestrogen metabolites predict breast cancer? Guernsey III cohort follow-up.” Br J Cancer. Nov;78(9): 1250–1255.
26 The role of estrogen in protecting brain function is still not understood, but it is clearly important for men as well as for women. V. Bisagno, R. Bowman, and V. Luine. 2003. “Functional aspects of estrogen neuroprotection.” Endocrine. Jun 1;21(1): 33–41; D. F. Swaab et al. 2003. “Sex differences in the hypothalamus in the different stages of human life.” Neurobiol Aging. May 1;24(Suppl 1): S1–S16, discussion, S17–S19.
27 A. Vincent and L. A. Fitzpatrick. 2000. “Soy isoflavones: are they useful in menopause?” Mayo Clin Proc. Nov;75(11): 1174–1184.
28 T. Horiuchi et al. 2000. “Effect of soy protein on bone metabolism in postmenopausal Japanese women.” Osteoporos Int. 11(8): 721–724; Y. Somekawa et al. 2001. “Soy intake related to menopausal symptoms, serum lipids, and bone mineral density in postmenopausal Japanese women.” Obstet Gynecol. Jan;97(1): 109–115.
29 One randomized crossover study examined the effects of three different soy diets on 18 healthy postmenopausal women. “When compared with baseline values, consumption of all three soy diets . . . decreased the ratio of genotoxic:total estrogens. These data suggest that both isoflavones and other soy constituents may exert cancer-preventative effects in postmenopausal women by altering estrogen metabolism away from genotoxic metabolites toward inactive metabolites.” X. Xu et al. 2000. “Soy consumption alters endogenous estrogen metabolism in postmenopausal women.” Cancer Epidemiol Biomarkers Prev. Aug;9: 781–786. See also L. A. Fitzpatrick. 2003. “Soy isoflavones: hope or hype?” Maturitas. March&14;44(Suppl 1): S21–29; T. Kishida et al. 2000. “Effect of dietary soy isoflavone aglycones on the urinary 16alpha-to-2-hydroxyestrone ratio in C3H/HeJ mice.” Nutr Cancer. 38(2): 209–214.
30 U.S. Soyfoods Directory; www.soyfoods.com/nutrition/isoflavoneconcentration.html.
31 F. Kronenberg and A. Fugh-Berman. 2002. “Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials.” Ann Intern Med. Nov 19;137(10): 805–813.
32 In the mid-1990s, researchers at Johns Hopkins established a link in animal studies between chemicals found in broccoli and protection against cancer. Since then, a number of studies have looked at the beneficial effects for people of cruciferous vegetables.
One study focused on why Polish women in the Midwest are more likely to develop breast cancer than their relatives in Europe. The answer may be in the cabbage, which is a cruciferous vegetable that the European Poles eat. Researchers from the University of Illinois at Urbana–Champaign “stimulated test-tube colonies of human breast-cancer cells with estrogen, then added extracts of plain cabbage, sauerkraut, or acidified brussels sprouts.” At higher concentrations, each extract “not only slowed the growth of estrogen-fed cells but also blocked estrogen’s ability to turn on a particular gene.” Though the study’s findings do not point conclusively to the agent in the vegetables that is at work, the findings do suggest “these foods might offer even more ‘potentially important’ agents and point toward a new class of drugs to reduce cancer risk.” J. Raloff. 2001. “Fighting cancer from the cabbage patch.” Science News. Mar 3;159(9); www.sciencenews.org/20010303/food.asp. For the study itself, see Y. H. Ju et al. 2000. “Estrogenic effects of extracts from cabbage, fermented cabbage, and acidified brussels sprouts on growth and gene expression of estrogen-dependent human breast cancer (MCF-7) cells.” J Agricultural Food Chem. Oct;48: 4628.
See also, G. Murillo and R. G. Mehta. 2001. “Cruciferous vegetables and cancer prevention.” Nutr Cancer. 41(1–2): 17–28; J. H. Fowke, C. Longcope, and J. R. Hebert. 2000. “Brassica vegetable consumption shifts estrogen metabolism in healthy postmenopausal women.” Cancer Epidemiol Biomarkers Prev. Aug;9(8): 773–779.
33 M. S. Brignall. 2001. “Prevention and treatment of cancer with indole-3-carbinol.” Altern Med Rev. Dec;6(6): 580–589.
34 J. R. Lee. 1999. What Your Doctor May Not Tell You About Premenopause. New York: Warner Books.
35 H. B. Leonetti et al. 1999. “Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss.” Obstet Gynecol. Aug;94(2): 225–228.
36 Ibid. See also B. G. Wren et al. 2003. “Transdermal progesterone and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, moods, and quality of life for postmenopausal women.” Menopause. Jan–Feb;10(1): 13–18.
37 “p53, a tumor suppressor gene, is a target of genetic alternations in many human and animal cancers. Compared to normal tissues, cancer tissues overexpress mutant p53 protein thus allowing their detection by a number of immunochemical procedures.” S. Haga et al. 2001. “Overexpression of the p53 gene product in canine mammary tumors.” Oncol Rep. Nov 1;8(6): 1215–1219. See also G. R. Sahu et al. 2002. “Rearrangement of p53 gene with overexpressed p53 protein in primary cervical cancer.” Oncol Rep. March 1;9(2): 433–437; V. K. Moudgil et al. 2001. “Hormonal regulation of tumor suppressor proteins in breast cancer cells.” J Steroid Biochem Mol Biol. Jan–Mar;76(1–5): 105–117.
38 K. J. Chang et al. 1995. “Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo.” Fertil Steril. Apr;63(4): 785–791.
39 S. Shantha et al. 2002. “Natural vaginal progesterone is associated with minimal psychological side effects: a preliminary study.” J Women’s Health Gend Based Med. Dec;10(10): 991–997 and S.Ferrero et al. 2002. “Vaginal micronized progesterone in continuous hormone replacement therapy. A prospective randomized study.” Minerva Gynecol. Dec;54(6): 519–530.
40 E. Darj et al. 1993. “Liver metabolism during treatment with estradiol and natural progesterone.” Gynecol Endocrinol. Jun;7(2): 111–114.
41 R. D. Langer. 1999. “Micronized progesterone: a new therapeutic option.” Int J Fertil Women’s Med. Mar–Apr;44(2): 67–73.
42 J. L. Shifren et al. 2000. “Transdermal testosterone treatment in women with impaired sexual function after oophorectomy.” N Engl J Med. Sep 7;343(10): 682–688.
43 E. Wespes and C. C. Schulman. 2002. “Male andropause: myth, reality, and treatment.” Int J Impot Res. Feb;14(Suppl 1): S93–S98.
44 J. P. Heaton and A. Morales. 2001. “Andropause—a multisystem disease.” Can J Urol. Apr;8(2): 1213–1222.
45 Shortly after the introduction of Proscar, Merck and Company introduced Propecia, which is identical to Proscar, only in a 1-mg rather than a 5-mg strength, as a treatment for male pattern baldness.
46 F. Debruyne et al. 2002. “Comparison of a phytotherapeutic agent (Permixon) with an alpha-blocker (tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study.” Eur Urol. May;41(5): 497–507; G. Campault et al. 1984. “A double-blind trial of an extract of the plant seronoa repens in benign prostatic hyperplasia.” Br. J. Clin. Pharm. 18: 461.
47 G. S. Gerber. 2000. “Saw palmetto for the treatment of men with lower urinary tract symptoms.” J Urol. May;163(5): 1408–1412.
48 L. B. Nieuwoudt et al. 1990. “Correlation between the macromolecular effects of estradiol and catecholestradiols and the total prostatic catecholestrogen concentration.” Clin Physiol Biochem. 8(5): 231–237.
49 A. M. Nakhla et al. 1994. “Estradiol Causes the Rapid Accumulation of cAMP in Human Prostate.” Proc Natl Acad Sci USA. June 7; 91 (12): 5402–5405.
50 B. T. Ashok et al. 2001. “Abrogation of estrogen-mediated cellular and biochemical effects by indole-3-carbinol.” Nutr Cancer. 41(1–2): 180–187; J. J. Michnovicz, H. Adlercreutz, and H. L. Bradlow. 1997. “Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans.” J Natl Cancer Inst. May 21;89(10): 718–723.
51 K. J. Auborn et al. 2003. “Indole-3-carbinol is a negative regulator of estrogen.” J Nutr. 133(7 Suppl): 2470S–2475S.
52 H. J. Jeong et al. 1999. “Inhibition of aromatase activity by flavonoids.” Arch Pharm Res. Jun;22(3): 309–312.
53 P. Taxel et al. 2001. “The effect of aromatase inhibition on sex steroids, gonadotropins, and markers of bone turnover in older men.” J Clin Endocrinol Metab. Jun;86(6): 2869–2874.
54 J. S. Bland. 2002. Nutritional Endocrinology: Breakthrough Approaches for Improving Adrenal and Thyroid Function. Gig Harbor, Washington: Metagenics Educational Programs, pp. 141–142.
55 A. T. Guay et al. 2003. “Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit?” Int J Impot Res. Jun;15(3): 156–165.
56 As one study concluded, “epidemiological studies provide no clues that the levels of circulating androgen are correlated with or predict prostate disease. Similarly, androgen replacement studies in men do not suggest that these men suffer in a higher degree from prostate disease than control subjects. It seems a defensible practice to treat aging men with androgens if and when they are testosterone-deficient, but long-term studies including sufficient numbers of men are needed.” L. Gooren. 2003. “Androgen deficiency in the aging male: benefits and risks of androgen supplementation.” J Steroid Biochem Mol Biol. Jun;85(2–5): 349–355. See also A. Morales. 2002. “Androgen replacement therapy and prostate safety.” Eur Urol. Feb;41(2): 113–120.
57 J. E. Morley. 2003. “The need for a men’s health initiative.” J Gerontol A Biol Sci Med Sci. 58: 614–617.

Chapters: 1-5, 6-10, 11-15, 21-23