18. Leonetti, H., et al. (1999). Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol, 94, 227–228.
19. Stearns, V., Beebe, K. L., Iyengar, M., & Dube, E. (2003). Paroxetine controlled release in the treatment of menopausal hot flashes: A randomized controlled trial. JAMA, 289, 2827–2834; Loprinzi, C. L., Sloan, J. A., Perez, E. A., et al. (2002). Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol, 20, 1578–1583; Loprinzi, C. L., Kugler, J. W., Sloan, J. A., et al. (2000). Venlafaxine in management of hot flashes in survivors of breast cancer: A randomized controlled trial. Lancet, 356, 2059–2063.
20. Goldberg, R. M., Loprinzi, C. L., O’Fallon, J. R., et al. (1994). Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol, 12, 155–158.
21. Irvin, J. H., Domar, A. D., Clark, C., Zuttermeister, P. C., & Friedman, R. (1996). The effects of relaxation response training on menopausal symptoms. J Psychosom Obstet Gynecol, 17, 202–207; Wijima, K., Melin, A., Nedstrand, E., & Hammar, M. (1997). Treatment of menopausal symptoms with applied relaxation: A pilot study. J Behav Ther Exp Psychiatry, 28, 251–261.
22. Freedman, R. R., & Woodward, S. (1992). Behavioral treatment of menopausal hot flashes: Evaluation by ambulatory monitoring. Am J Obstet Gynecol, 167, 436–439; Stevenson, D. W., & Delprato, D. J. (1983). Multiple component self-control program for menopausal hot flashes. J Behav Ther Exp Psychiatry, 14 (2), 137–140; Domar, A. D., & Dreher, H. (1997). Healing Mind, Healthy Woman, 291–292. New York: Delta.
23. Ghent, W. (1993). Iodine replacement in fibrocystic disease of the breast. Can J Surg, 36, 453–460; Kessler, J. H. (2004). The effect of supraphysiologic levels of iodine on patients with cyclic mastalgia. Breast J, 10 (4), 328–336.
Chapter 5: Hormone Therapy
1. Writing Group for the Women’s Health Initiative Investigators (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal result from the Women’s Health Initiative randomized controlled trial. JAMA, 288, 327–333.
2. Lacey, J. V., et al. (2002). Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA, 288, 334–341.
3. Grodstein, F., Manson, J. E., & Stampfer, M. J. (2006). Hormone therapy and coronary heart disease: The role of time since menopause and age at hormone initiation. J Womens Health (Larchmt), 15 (1), 35–44.
4. Toh, S., et al. (2010). Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: Does the increased risk ever disappear? A randomized trial. Ann Intern Med, 152 (4), 211–217.
5. North American Menopause Society. (2010). Estrogen and progestogen use in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause, 17, 242–255.
6. Shen, L., Qiu, S., Chen, Y., Zhang, F., van Breemen, R. B., Nikolic, D., &Bolton, J. L. (1998). Alkylation of 2’-deoxynucleosides and DNA by the Premarin metabolite 4-hydroxyequilenin semiquinone radical. Chem Res Toxicol, 11, 94–101; Bhavnani, B. (1998). Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: Chemistry and metabolism. Proc Soc Biol Med, 217 (1), 6–16; Zhang, F., et al. (1999). The major metabolite of equilin, 4-hydroxyequilin, autoxidizes to an ó-quinone which isomerizes to the potent cytotoxin 4-hydroxyequilenin-ó-quinone. Chem Res Toxicol, 12, 204–213.
7. Cole, W., et al. (June 26, 1995). The estrogen dilemma. Time, 46–53 (cover story).
8. Brody, J. (Sept. 3, 2002). Sorting through the confusion about hormone replacement therapy. New York Times.
9. Loucks, T. L., & Berga, S. L. (2009). Does postmenopausal estrogen use confer neuroprotection? Semin Reprod Med, 27 (3), 260–274.
10. Fournier, A., Berrino, F., & Clavel-Chapelon, F. (2008). Unequal risks for breast cancer associated with different hormone replacement therapies: Results from the E3N Cohort Study. Breast Cancer Res Treat, 107, 103–111.
11. Ninth Annual American Association for Cancer Research Frontiers in Cancer Prevention Research Conference, Philadelphia, Nov. 7–10, 2010.
12. Shaak, C. Personal communication about Dr. Shaak’s fifteen years of ongoing clinical research on the restoration of early luteal phase hormone levels in menopausal women by transdermal application of progesterone, estradiol, and testosterone. Dr. Shaak suggests that a woman’s exact dosage be determined by the combination of her symptoms, a physical exam, and lab tests. (For further information, contact Dr. Shaak at WomanWell, 405 Great Plain Avenue, Needham, MA 02492. Tel.: 781-453-0321; www.WomenWell.net); Hargrove, J., et al. (1998). Absorption of estradiol and progesterone delivered via Jergens lotion used as hormone replacement therapy. Poster session presented at the annual meeting of the North American Menopause Society, Philadelphia.
13. Follingstad, A. (1978). Estriol, the forgotten hormone. JAMA, 239 (1), 29–39; Lemon, H. (1977). Clinical and experimental aspects of the antimammary carcinogenic activity of estriol. Front Horm Res, 5 (1), 155–173; Lemon, H. (1975). Estriol prevention of mammary carcinoma induced by 7, 12-dimethylbenzathracene and procarbazine. Cancer Res, 35, 1341–1353; Lemon, H. (1973). Oestriol and prevention of breast cancer. Lancet, 1 (802), 546–547; Lemon, H. (1980). Pathophysiologic considerations in the treatment of menopausal patients with oestrogens: The role of oestriol in the prevention of mammary cancer. Acta Endocrinol Suppl (Copenh), 233, 17–27; Lemon, H., Wotiz, H., Parsons, L., et al. (1966). Reduced estriol excretion in patients with breast cancer prior to endocrine therapy. JAMA, 196, 1128–1136.
14. Carroll, N., et al. (May 2009). Postmenopausal restoration of the estradiol/ estrone ratio reduces severity of vasomotor symptoms. Paper presented at the annual meeting of the American College of Obstetricians and Gynecologists, Chicago, IL; Heimer, G. M., & Englund, D. E. (1992). Effects of vaginally administered oestriol on postmenopausal urogenital disorders: A cytohormonal study. Maturitas, 3, 171–179; Iosif, C. S. (1992). Effects of protracted administration of estriol on the lower urinary tract in postmenopausal women. Arch Gynecol Obstet, 3 (251), 115–120; Kirkengen, A. L., Andersen, P., Gjersoe, E., et al. (June 1992). Oestriol in the prophylactic treatment of recurrent urinary tract infections in postmenopausal women. Scand J Prim Health Care, 139–142; Raz, K., & Stamm, W. (1993). A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med, 329, 753–756.
15. American College of Obstetricians and Gynecologists (2004). Cognition and dementia. Obstet Gynecol, 104 (suppl. 4), 25S–40S.
16. Speroff, L., et al. (1999). Clinical Gynecologic Endocrinology and Infertility (6th ed.), 56–64. Philadelphia: Lippincott, Williams & Wilkins.
17. Speroff, L. (Sept. 1999). Commentary: Postmenopausal therapy reduces the risk of colorectal cancer. OB/GYN Alert, 35.
18. Love, R. R., Cameron, L., & Connell, B. L. (1991). Symptoms associated with tamoxifen treatment in postmenopausal women. Arch Intern Med 151, 1842–1847.
19. Li, C. I., et al. (2009). Adjuvant hormonal therapy for breast cancer and risk of hormone receptor-specific subtypes of contralateral breast cancer. Cancer Res, 69, 6865–6870.
20. Koenig, H., et al. (1995). Progesterone synthesis and myelin formation by Schwann cells. Science, 268, 1500–1503.
21. When I was a resident in OB-GYN at St. Margaret’s Hospital in Boston in the mid-1970s, I routinely saw women in their late thirties and forties who had a number of children and continued to get pregnant year after year, until they welcomed a hysterectomy as a way to avoid further pregnancies. Their lives, beliefs, and biology stand in sharp contrast to today’s thirty-six-year-old professional woman who started worrying as soon as she turned thirty-five that she wouldn’t be able to get pregnant. Our beliefs have subtle yet powerful effects on our biology—effects that are confirmed by research. Brant Secunda is an American-born shaman who was trained by the Huichol Indians, who live in a remote region of Mexico. Brant reports that Huichol women routinely get pregnant in their fifties and some even in their sixties. The work of Dr.
Alice Domar, of the Beth Israel Deaconess Medical Center and the Mind/Body Medical Institute, reports a 50 percent increase in pregnancy rates in previously infertile women, most of whom are professionals in their thirties and forties, when they participate in programs char-acterized by group support, deep relaxation, and attention to self-care. These pregnancies become possible because of the ability of the mind and beliefs to effect hormonal levels that better favor conception.
22. Beral, V., et al. (2011). Breast cancer risk in relation to the interval between menopause and starting hormone therapy. J Nat Cancer Inst, 103, 296–305.
23. Fournier, A., Berrino, F., & Clavel-Chapelon, F. (2008). Unequal risks for breast cancer associated with different hormone replacement therapies: Results from the E3N Cohort Study. Breast Cancer Res Treat, 107, 103–111.
24. Fournier, A., et al. (2009). Estrogen-progestogen menopausal hormone therapy and breast cancer: Does delay from menopause onset to treatment initiation influence risks? J Clin Oncol, 27, 5138–5143.
25. Hermsmeyer, K., et al. (2008). Cardiovascular effects of medroxyprogesterone acetate and progesterone: A case of mistaken identity? Nat Clin Prac Cardiovasc Med, 5, 387–395.
26. Stanczyk, F. Z., Paulson, R. J., & Roy, S. (2005). Percutaneous administration of progesterone: Blood levels and endometrial protection. Menopause, 12 (2), 232–237.
27. Hully, S., et al. (1998). Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA, 280, 605–618; Sullivan, J. M., et al. (1995). Progestin enhances vasoconstrictor responses in postmenopausal women receiving estrogen replacement therapy. Menopause, 4, 193–197; Williame, J. K., et al. (1994). Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomologous monkeys. J Am Coll Cardiol, 24, 1757–1761; Sarrel, P. (1999). The differential effects of oestrogens and progestins on vascular tone. Human Reproduction Update, 5 (3), 205–209.
28. Toh, S., et al. (2010). Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: Does the increased risk ever disappear? A randomized trial. Ann Intern Med, 152 (4), 211–217.
29. Tang, G. W. K. (1994). The climacteric of Chinese factory workers. Maturitas, 19, 177–182.
30. Hammond, C. B. (1994). Women’s concerns with hormone replacement therapy—compliance issues. Fertil Steril, 62 (suppl. 2), 157S–160S.
31. Hermsmeyer, R. K., Thompson, T. L., Pohost, G. M., & Kaski, J. C. (2008). Cardiovascular effects of medroxyprogesterone acetate and progesterone: A case of mistaken identity? Nat Clin Prac Cardiovasc Med, 5, 387–395.
32. Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial (1995). Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA, 273, 199–206.
33. American College of Obstetricians and Gynecologists (2004). Coronary heart disease. Obstet Gynecol, 104 (suppl. 4), 415–485.
34. Yaffe, K., Lui, L.-Y., Grady, D., Cauley, J., Kramer, J., & Cummings, S. R. (2000). Cognitive decline in women in relation to non-protein-bound estradiol concentrations. Lancet, 356 (9231), 708–712.
35. Grodstein, F., Newcomb, P. A., & Stampfer, M. J. (1999). Postmenopausal hormone therapy and the risk of colorectal cancer: A review and metaanalysis. Am J Med, 106 (5), 574–582.
36. Hedrick, R. E., et al. (2009). Transdermal estradiol gel 0.1% for the treatment of vasomotor symptoms in postmenopausal women. Menopause, 16, 132–140.
37. Kolata, G. (July 9, 2002). Citing risks, U.S. will halt study of drugs for hormones. New York Times.
Chapter 6: Foods and Supplements to Support the Change
1. Hudson, T. (1994). A pilot study using botanical medicine in the treatment of menopausal symptoms. Portland, Oregon, National College of Naturopathic Medicine and the Bastyr University of Natural Health Sciences.
2. Tyler, V. E. (1993). The Honest Herbal: A Sensible Guide to the Use of Herbs and Related Remedies (3rd ed.). Binghamton, NY: Haworth Press.
3. Elghamry, M. I., & Shihata, I. M. (1965). Biological activity of phytoestrogens. Planta Med, 13, 352–357.
4. Knight, D., & Eden, J. (1996). A review of the clinical effects of phytoestrogens. Part 2. Obstet Gynecol, 87 (5), 897–904; Kaldas, R. S., & Hughes, C. L. (1989). Reproductive and general metabolic effects of phytoestrogens in mammals. Reprod Toxicol, 3, 81–89.
5. Rose, D. P. (1992). Dietary fiber, phytoestrogens, and breast cancer. Nutrition, 8, 47–51.
6. Tamaya, T., et al. (1986). Inhibition by plant herb extracts of steroid bindings in uterus, liver, and serum of the rabbit. Acta Obstet Gynecol Scand, 65, 839–842.
7. Yoshiro, K. (1985). The physiological actions of tan-kwei and cnidium. Bull Oriental Healing Arts Institute USA, 10, 269–278; Harada, M., Suzuki, M., & Ozaki, Y. (1984). Effects of Japanese Angelica root and peony root on uterine contraction in the rabbit in situ. J Pharmacol Dynam, 7, 304–311; Zhu, D. P. O. (1987). Dong quai. Am J Chinese Med, 15, 117–125.
8. Bohnert, K.-J. (Spring 1997). The use of Vitex agnus-castus for hyperprolactinemia. Q Rev Natural Med, 19–20; American Botanical Council (1992). Kommission E monograph: Agnus casti fructus (chaste tree fruits). Fort Worth, TX.
9. Duker, E. M., et al. (1991). Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Med, 57, 420–424, 1991.
10. Geller, S. E., et al. (2009). Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: A randomized controlled trial. Menopause, 16 (6), 1156–1166.
11. Wuttke, W., et al. (2003). The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: Effects on menopause symptoms and bone markers. Maturitas, 44, S67–S77; Hernandez Munoz, G., & Pluchino, S. (2003). Cimicifuga racemosa for the treat-ment of hot flushes in women surviving breast cancer, Maturitas, 44, S59–S65.
12. Hudson, T. (2008–2009). Maca: New insights on an ancient plant. Integr Med, 7 (6), 54–57.
13. Garcia, J. T., Gonzaga, F., Tan, D., Ng, T. Y., Oei, P. L., & Chan, C. W. B. (Nov. 19, 2009; epub ahead of print). Use of a multibotanical (Nutrafem) for the relief of menopausal vasomotor symptoms: A double-blind, placebo-controlled study. Menopause.
14. Maevsky, E. I., et al. (2008). A succinate-based composition reverses menopausal symptoms without sex hormone replacement therapy. Advances in Gerontology, 21, 298–305.
15. Manonai, J., et al. (2008). Effects and safety of Pueraria mirifica on lipid profiles and biochemical markers of bone turnover rates in healthy postmenopausal women. Menopause, 15 (3), 530–535; Urasopon, N., et al. (2007). Pueraria mirifica, a phytoestrogen-rich herb, prevents bone loss in orchidectomized rats. Maturitas, 56, 3, 322–331.
16. Chandeying, V., & Sangthawan, M. (2007). Efficacy comparison of Pueraria mirifica (PM) against conjugated equine estrogen (CEE) with/without medroxyprogesterone acetate (MPA) in the treatment of climacteric symptoms in perimenopausal women: Phase III study. J Med Assoc Thai, 90, 9, 1720–1726.
17. Personal correspondence with C. Deachapunya, Department of Physiology, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand; Poonyachoti, S. et al. (2008). Effects of Pueraria mirifica, phystoestrogens and 17b-estradiol on growth and expression of ERA in primary culture of porcine endometrial epithelial cells. Acta Horticulturae (ISHS) 786, 67–72.
18. Ramnarine, S., MacCallum, J., & Ritchie, M. (2009). Phyto-oestrogens: Do they have a role in breast cancer therapy? Proc Nutr Soc, 68, E93.
19. Cassidy, A., Bingham, S., & Setchell, K. (1994). Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women. Am J Clin Nutr, 60, 333–340; Anderson, J. W., et al. (1998). Effects of soy protein on renal function and proteinuria in patients with type 2 diabetes. Am J Clin Nutr, 68 (suppl. 6), 1347S–1353S.
20. Wong, W. W., Heird, W. C., & Smith, E. O. (Apr. 2000). Potential health benefits of soy in postmeno
pausal women. Data presented at the Experimental Biology Meeting, San Diego, CA.
21. Foth, D., & Cline, J. M. (1998). Effects of mammalian and plant estrogens on mammary glands and uteri of macaques. Am J Clin Nutr, 68 (suppl.), 1413S–1471S.
22. Scheiber, M., & Setchell, K. (June 1999). Dietary soy isoflavones favorably influence lipids and bone turnover in healthy postmenopausal women. Endocrine Society’s 81st Annual Meeting Synopsis.
23. Taku, K., et al. (2007). Soy isoflavones lower serum total and LDL cholesterol in humans: A meta-analysis of 11 randomized controlled trials. Am J Clin Nutr, 85 (4), 1148–1156; Zhuo, X. G., Melby, M. K., & Watanabe, S. (2004). Soy isoflavone intake lowers serum LDL cholesterol: A meta-analysis of 8 randomized controlled trials in humans. J Nutr, 134, 2395–2400.
24. Anderson, J. W., Johnstone, B. M., & Cook-Newell, M. E. (1995). Metaanalysis of the effects of soy protein intake on serum lipids. N Engl J Med, 333 (5), 276–282.
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