Life Extension Magazine

Life Extension Magazine November 2013

As We See It

Surprise Findings in Estrogen Debate

By William Faloon

References

  1. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002 July 17;288(3):321–33.
  2. Available at: http://www.lef.org/magazine/mag96/96jan1b.htm?source=search&key=synthetic%20progestin. Accessed August 5, 2013.
  3. Available at: http://www.lef.org/magazine/mag98/jun98_cover.htm?source=search&key=synthetic%20progestin. Accessed August 5, 2013.
  4. Available at: http://www.lef.org/magazine/mag98/jun98_cover2.html?source=search&key=synthetic%20progestin. Accessed August 5, 2013.
  5. Available at: http://www.lef.org/magazine/mag99/june99-report1.html?source=search&key=synthetic%20progestin. Accessed August 5, 2013.
  6. Available at: http://www.lef.org/magazine/mag2002/dec2002_report_hormone_01.html. Accessed August 5, 2013.
  7. Available at: http://www.lef.org/magazine/mag2002/dec2002_cover_premarin_01.htm?source=search&key =synthetic%20progestin. Accessed August 5, 2013.
  8. Available at: http://www.lef.org/magazine/mag2003/jun2003_report_female_01.htm?source=search&key =synthetic%20progestin. Accessed August 5, 2013.
  9. Available at: http://www.lef.org/magazine/mag2006/apr2006_report_progesterone_01.htm?source=search&key =synthetic%20progestin. Accessed August 5, 2013.
  10. Available at: http://www.lef.org/magazine/mag2009/oct2009_Bioidentical-Hormones_06.htm. Accessed August 12,2013.
  11. Sarrel PM, Njike VY, Vinante V, Katz DL. The mortality toll of estrogen avoidance: An analysis of excess deaths among hysterectomized women aged 50 to 59 years. Am J Public Health. 2013 Jul 18.
  12. Salpeter SR, Cheng J, Thabane L, Buckley NS, Salpeter EE. Bayesian meta-analysis of hormone therapy and mortality in younger postmenopausal women. Am J Med. 2009 Nov;122(11):1016-22.
  13. Horstman AM, Dillon EL, Urban RJ, Sheffield-Moore M. The role of androgens and estrogens on healthy aging and longevity. J Gerontol A Biol Sci Med Sci. 2012 Nov;67(11):1140-52.
  14. Birge SJ. The use of estrogen in older women. Clin Geriatr Med. 2003 Aug;19(3):617-27, viii.
  15. Available at: http://www.medicinenet.com/menopause/article.htm. Accessed August 5, 2013.
  16. Vajaranant TS, Pasquale LR. Estrogen deficiency accelerates aging of the optic nerve. Menopause. 2012 Aug;19(8):942-7.
  17. Pasquale LR, Rosner BA, Hankinson SE, Kang JH. Attributes of female reproductive aging and their relation to primary open-angle glaucoma: a prospective study. J Glaucoma. 2007 Oct-Nov;16(7):598-605.
  18. Altintaş O, Caglar Y, Yüksel N, Demirci A, Karabaş L. The effects of menopause and hormone replacement therapy on quality and quantity of tear, intraocular pressure and ocular blood flow. Ophthalmologica. 2004 Mar-Apr;218(2):120-9.
  19. Rocca WA, Grossardt BR, Shuster LT, Stewart EA. Hysterectomy, oophorectomy, estrogen, and the risk of dementia. Neurodegener Dis. 2012 10(1-4):175-8.
  20. Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer’s disease in women. Am J Epidemiol. 1994 Aug 1;140(3):256-61.
  21. Nappi RE, Sinforiani E, Mauri M, Bono G, Polatti F, Nappi G. Memory functioning at menopause: impact of age in ovariectomized women. Gynecol Obstet Invest. 1999 47(1):29-36.
  22. Aydin A, Kenar H, Atmaca H, et al. The short- and long- term effects of estrogen deficiency on apoptosis in musculoskeletal tissues: an experimental animal model study. Arch Iran Med. 2013 May;16(5):271-6.
  23. Syed FA, Mödder UI, Roforth M, et al. Effects of chronic estrogen treatment on modulating age-related bone loss in female mice. J Bone Miner Res. 2010 Nov;25(11):2438-46.
  24. Novella S, Dantas AP, Segarra G, Medina P, Hermenegildo C. Vascular aging in women: Is estrogen the fountain of youth? Front Physiol. 2012;3:165.
  25. Bairey Merz CN, Johnson BD, Sharaf BL, et al. Hypoestrogenemia of hypothalamic origin and coronary artery disease in premenopausal women: a report from the NHLBI-sponsored WISE study. J Am Coll Cardiol. 2003 Feb 5;41(3):413-9.
  26. Seeman E. Estrogen, androgen, and the pathogenesis of bone fragility in women and men. Curr Osteoporos Rep. 2004 Sep;2(3):90-6.
  27. Lynch C. Vaginal estrogen therapy for the treatment of atrophic vaginitis. J Womens Health (Larchmt). 2009 Oct;18(10):1595-606.
  28. Available at: http://www.obgmanagement.com/index.php?id=20667&tx_ttnews[tt_news]=175742. Accessed August 6, 2013.
  29. Available at: http://www.clinicaladvisor.com/tissue-changes-associated-with-vaginal-atrophy/article/177880/#. Accessed August 6, 2013.
  30. Maltais ML, Desroches J, Dionne IJ. Changes in muscle mass and strength after menopause. J Musculoskelet Neuronal Interact. 2009 Oct-Dec;9(4):186-97.
  31. Lowe DA, Baltgalvis KA, Greising SM. Mechanisms behind estrogen’s beneficial effect on muscle strength in females. Exerc Sport Sci Rev. 2010 Apr;38(2):61-7.
  32. Shu YY, Maibach HI. Estrogen and skin: therapeutic options. Am J Clin Dermatol. 2011 Oct 1;12(5):297-311.
  33. Hall G, Phillips TJ. Estrogen and skin: the effects of estrogen, menopause, and hormone replacement therapy on the skin. J Am Acad Dermatol. 2005 Oct;53(4):555-68.
  34. Anderson GL, Limacher M, Assaf AR, et al. Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004 Apr 14;291(14):1701-12.
  35. Goletiani NV, Keith DR, Gorsky SJ. Progesterone: review of safety for clinical studies. Exp Clin Psychopharmacol. 2007 Oct;15(5):427-44.
  36. Otto C, Fuchs I, Vonk R, Fritzemeier KH. Comparative analysis of the uterine and mammary gland effects of progesterone and medroxyprogesterone acetate. Maturitas. 2010 Apr;65(4):386-91.
  37. Bhavnani BR. Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism. Proc Soc Exp Biol Med. 1998 Jan;217(1):6-16.
  38. Available at: http://umm.edu/health/medical/altmed/herb/wild-yam. Accessed August 7, 2013.
  39. Formby B, Wiley TS. Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53. Ann Clin Lab Sci. 1998 Nov-Dec;28(6):360-9.
  40. Campagnoli C, Clavel-Chapelon F, Kaaks R, Peris C, Berrino F. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem Mol Biol. 2005 Jul;96(2):95-108.
  41. Holtorf K. The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Postgrad Med. 2009 Jan;121(1):73-85.
  42. Wood CE, Register TC, Lees CJ, Chen H, Kimrey S, Cline JM. Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat. 2007 Jan;101(2):125-34.
  43. Zhou J, Yu Q, Chen R, et al. Medroxyprogesterone acetate-driven increase in breast cancer risk might be mediated via cross-talk with growth factors in the presence of progesterone receptor membrane component-1. Maturitas. 2013 Jul 12.
  44. Chlebowski RT, Manson JE, Anderson GL, et al. Estrogen plus progestin and breast cancer incidence and mortality in the Women’s Health Initiative Observational Study. J Natl Cancer Inst. 2013 Apr 17;105(8):526-35.
  45. Liang Y, Benakanakere I, Besch-Williford C, Hyder RS, Ellersieck MR, Hyder SM. Synthetic progestins induce growth and metastasis of BT-474 human breast cancer xenografts in nude mice. Menopause. 2010 Sep-Oct;17(5):1040-7.
  46. Baker VL. Alternatives to oral estrogen replacement. Transdermal patches, percutaneous gels, vaginal creams and rings, implants, other methods of delivery. Obstet Gynecol Clin North Am. 1994 Jun;21(2):271-97.
  47. Vehkavaara S, Silveira A, Hakala-Ala-Pietilä T, et al. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost. 2001 Apr;85(4):619-25.
  48. L’hermite M. HRT optimization, using transdermal estradiol plus micronized progesterone, a safer HRT. Climacteric. 2013 Aug;16 Suppl 1:44-53.
  49. Novensa L, Selent J, Pastor M, Sandberg K, Heras M, Dantas AP. Equine estrogens impair nitric oxide production and endothelial nitric oxide synthase transcription in human endothelial cells compared with the natural 17{beta}-estradiol. Hypertension. 2010 Sep;56(3):405-11.
  50. Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Effect of medroxyprogesterone acetate on endothelium-dependent vasodilation in postmenopausal women receiving estrogen. Circulation. 2001 Oct 9;104(15):1773-8.
  51. Miyagawa K, Rösch J, Stanczyk F, Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nat Med. 1997 Mar;3(3):324-7.
  52. Fowke JH, Longcope C, Hebert JR. Brassica vegetable consumption shifts estrogen metabolism in healthy postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2000 Aug;9(8):773-9.
  53. Michnovicz JJ, Adlercreutz H, Bradlow HL. Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J Natl Cancer Inst. 1997 May 21;89(10):718-23.
  54. Bortman P, Folgueira MA, Katayama ML, Snitcovsky IM, Brentani MM. Antiproliferative effects of 1,25-dihydroxyvitamin D3 on breast cells: a mini review. Braz J Med Biol Res. 2002 Jan;35(1):1-9.
  55. Lowe L, Hansen CM, Senaratne S, Colston KW. Mechanisms implicated in the growth regulatory effects of vitamin D compounds in breast cancer cells. Recent Results Cancer Res. 2003;164:99-110.
  56. Holick MF. Vitamin d, sunlight and cancer connection. Anticancer Agents Med Chem. 2013 Jan 1;13(1):70-82.
  57. Ory K, Lebeau J, Levalois C, et al. Apoptosis inhibition mediated by medroxyprogesterone acetate treatment of breast cancer cell lines. Breast Cancer Res Treat. 2001 Aug;68(3):187-98.
  58. Hofseth LJ, Raafat AM, Osuch JR, Pathak DR, Slomski CA, Haslam SZ. Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab. 1999 Dec;84(12):4559-65.
  59. Jeng MH, Parker CJ, Jordan VC. Estrogenic potential of progestins in oral contraceptives to stimulate human breast cancer cell proliferation. Cancer Res. 1992 Dec 1;52(23):6539-46.
  60. Kalkhoven E, Kwakkenbos-Isbrücker L, de Laat SW, van der Saag PT, van der Burg B. Synthetic progestins induce proliferation of breast tumor cell lines via the progesterone or estrogen receptor. Mol Cell Endocrinol. 1994 Jun;102(1-2):45-52.
  61. Papa V, Reese CC, Brunetti A, Vigneri R, Siiteri PK, Goldfine ID. Progestins increase insulin receptor content and insulin stimulation of growth in human breast carcinoma cells. Cancer Res. 1990 Dec 15;50(24):7858-62.
  62. Jordan VC, Jeng MH, Catherino WH, Parker CJ. The estrogenic activity of synthetic progestins used in oral contraceptives. Cancer. 1993 Feb 15;71(4 Suppl):1501-5.
  63. Catherino WH, Jeng MH, Jordan VC. Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism. Br J Cancer. 1993 May;67(5):945-52.
  64. Cline JM, Soderqvist G, von Schoultz E, Skoog L, von Schoultz B. Effects of conjugated estrogens, medroxyprogesterone acetate, and tamoxifen on the mammary glands of macaques. Breast Cancer Res Treat. 1998 Apr;48(3):221-9.
  65. Cline JM, Soderqvist G, von Schoultz E, Skoog L, von Schoultz B. Effects of hormone replacement therapy on the mammary gland of surgically postmenopausal cynomolgus macaques. Am J Obstet Gynecol. 1996 Jan;174(1 Pt 1):93-100.
  66. Menendez JA, Oza BP, Colomer R, Lupu R. The estrogenic activity of synthetic progestins used in oral contraceptives enhances fatty acid synthase-dependent breast cancer cell proliferation and survival. Int J Oncol. 2005 Jun;26(6):1507-15.
  67. Seeger H, Rakov V, Mueck AO. Dose-dependent changes of the ratio of apoptosis to proliferation by norethisterone and medroxyprogesterone acetate in human breast epithelial cells. Horm Metab Res. 2005 Aug;37(8):468-73.
  68. Murkes D, Conner P, Leifland K, et al. Effects of percutaneous estradiol-oral progesterone versus oral conjugated equine estrogens-medroxyprogesterone acetate on breast cell proliferation and bcl-2 protein in healthy women. Fertil Steril. 2011 Mar 1;95(3):1188-91.
  69. Wood CE, Register TC, Cline JM. Transcriptional profiles of progestogen effects in the postmenopausal breast. Breast Cancer Res Treat. 2009 Mar;114(2):233-42.
  70. Neubauer H, Ruan X, Schneck H, et al. Overexpression of progesterone receptor membrane component 1: possible mechanism for increased breast cancer risk with norethisterone in hormone therapy. Menopause. 2013 May;20(5):504-10.
  71. Murkes D, Lalitkumar PG, Leifland K, Lundström E, Söderqvist G. Percutaneous estradiol/oral micronized progesterone has less-adverse effects and different gene regulations than oral conjugated equine estrogens/medroxyprogesterone acetate in the breasts of healthy women in vivo. Gynecol Endocrinol. 2012 Oct;28 Suppl 2:12-5.
  72. Chang KJ, Lee TT, Linares-Cruz G, Fournier S, de Ligniéres B. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril. 1995 Apr;63(4):785-91.
  73. Foidart JM, Colin C, Denoo X, et al. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril. 1998 May;69(5):963-9.
  74. Mueck AO, Seeger H, Wallwiener D. Comparison of the proliferative effects of estradiol and conjugated equine estrogens on human breast cancer cells and impact of continuous combined progestogen addition. Climacteric. 2003 Sep;6(3):221-7.
  75. Inoh A, Kamiya K, Fujii Y, Yokoro K. Protective effects of progesterone and tamoxifen in estrogen-induced mammary carcinogenesis in ovariectomized W/Fu rats. Jpn J Cancer Res. 1985 Aug;76(8):699-704.
  76. Barrat J, de Lignières B, Marpeau L, et al. The in vivo effect of the local administration of progesterone on the mitotic activity of human ductal breast tissue. Results of a pilot study. J Gynecol Obstet Biol Reprod (Paris). 1990;19(3):269-74.
  77. Malet C, Spritzer P, Guillaumin D, Kuttenn F. Progesterone effect on cell growth, ultrastructural aspect and estradiol receptors of normal human breast epithelial (HBE) cells in culture. J Steroid Biochem Mol Biol. 2000 Jun;73(3-4):171-81.
  78. Laidlaw IJ, Clarke RB, Howell A, Owen AW, Potten CS, Anderson E. The proliferation of normal human breast tissue implanted into athymic nude mice is stimulated by estrogen but not progesterone. Endocrinology. 1995 Jan;136(1):164-71.
  79. van Leeuwen FE. Epidemiologic aspects of exogenous progestagens in relation to their role in pathogenesis of human breast cancer. Acta Endocrinol (Copenh). 1991;125 Suppl 1:13-26.
  80. Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005 Apr 10;114(3):448-54.
  81. Porch JV, Lee IM, Cook NR, Rexrode KM, Burin JE. Estrogen-progestin replacement therapy and breast cancer risk: the Women’s Health Study (United States). Cancer Causes Control. 2002 Nov;13(9):847-54.
  82. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008 Jan;107(1):103-11.
  83. Plu-Bureau G, Lê MG, Thalabard JC, Sitruk-Ware R, Mauvais-Jarvis P. Percutaneous progesterone use and risk of breast cancer: results from a French cohort study of premenopausal women with benign breast disease. Cancer Detect Prev. 1999;23(4):290-6.
  84. Micheli A, Muti P, Secreto G, et al. Endogenous sex hormones and subsequent breast cancer in premenopausal women. Int J Cancer. 2004 Nov 1;112(2):312-8.
  85. Cowan LD, Gordis L, Tonascia JA, Jones GS. Breast cancer incidence in women with a history of progesterone deficiency. Am J Epidemiol. 1981 Aug;114(2):209-17.
  86. Peck JD, Hulka BS, Poole C, Savitz DA, Baird D, Richardson BE. Steroid hormone levels during pregnancy and incidence of maternal breast cancer. Cancer Epidemiol Biomarkers Prev. 2002 Apr;11(4):361-8.
  87. Badwe RA, Wang DY, Gregory WM, et al. Serum progesterone at the time of surgery and survival in women with premenopausal operable breast cancer. Eur J Cancer. 1994;30A(4):445-8.
  88. Mohr PE, Wang DY, Gregory WM, Richards MA, Fentiman IS. Serum progesterone and prognosis in operable breast cancer. Br J Cancer. 1996 Jun;73(12):1552-5.
  89. Irvin W Jr, Muss HB, Mayer DK. Symptom management in metastatic breast cancer. Oncologist. 2011;16(9):1203-14.
  90. Available at: http://www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_06.pdf. Accessed August 7, 2013.
  91. Rosano GM, Webb CM, Chierchia S, et al. Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol. 2000 Dec;36(7):2154-9.
  92. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007 Feb 20;115(7):840-5.
  93. Register TC, Adams MR, Golden DL, Clarkson TB. Conjugated equine estrogens alone, but not in combination with medroxyprogesterone acetate, inhibit aortic connective tissue remodeling after plasma lipid lowering in female monkeys. Arterioscler Thromb Vasc Biol. 1998 Jul;18(7):1164-71.
  94. Levine RL, Chen SJ, Durand J, Chen YF, Oparil S. Medroxyprogesterone attenuates estrogen-mediated inhibition of neointima formation after balloon injury of the rat carotid artery. Circulation. 1996 Nov 1;94(9):2221-7.
  95. Adams MR, Register TC, Golden DL, Wagner JD, Williams JK. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol. 1997 Jan;17(1):217-21.
  96. Morey AK, Pedram A, Razandi M, et al. Estrogen and progesterone inhibit vascular smooth muscle proliferation. Endocrinology. 1997 Aug;138(8):3330-9.
  97. Houser SL, Aretz HT, Quist WC, Chang Y, Schreiber AD. Serum lipids and arterial plaque load are altered independently with high-dose progesterone in hypercholesterolemic male rabbits. Cardiovasc Pathol. 2000 Nov-Dec;9(6):317-22.
  98. Adams MR, Kaplan JR, Manuck SB, et al. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone. Arteriosclerosis. 1990 Nov-Dec;10(6):1051-7.
  99. Tall AR. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins. J Intern Med. 2008 Mar;263(3):256-73.
  100. Fåhraeus L, Larsson-Cohn U, Wallentin L. L-norgestrel and progesterone have different influences on plasma lipoproteins. Eur J Clin Invest. 1983 Dec;13(6):447-53.
  101. Larsson-Cohn U, Fåhraeus L, Wallentin L, Zador G. Lipoprotein changes may be minimized by proper composition of a combined oral contraceptive. Fertil Steril. 1981 Feb;35(2):172-9.
  102. Hirvonen E, Mälkönen M, Manninen V. Effects of different progestogens on lipoproteins during postmenopausal replacement therapy. N Engl J Med. 1981 Mar 5;304(10):560-3.
  103. Ottosson UB. Oral progesterone and estrogen/progestogen therapy. Effects of natural and synthetic hormones on subfractions of HDL cholesterol and liver proteins. Acta Obstet Gynecol Scand Suppl. 1984;127:1-37.
  104. Ottosson UB, Johansson BG, von Schoultz B. Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: a comparison between progestogens and natural progesterone. Am J Obstet Gynecol. 1985 Mar 15;151(6):746-50.
  105. Jensen J, Riis BJ, Strøm V, Nilas L, Christiansen C. Long-term effects of percutaneous estrogens and oral progesterone on serum lipoproteins in postmenopausal women. Am J Obstet Gynecol. 1987 Jan;156(1):66-71.
  106. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA. 1995 Jan 18;273(3):199-208.
  107. Available at: http://www.nia.nih.gov/health/publication/menopause. Accessed August 13, 2013.
  108. Available at: http://www.mayoclinic.com/health/perimenopause/DS00554. Accessed August 13, 2013.
  109. Available at: http://www.altmedrev.com/publications/10/1/36.pdf. Accessed August 13, 2013.
  110. Available at: http://www.liveto110.com/estrogen-dominance-syndrome/. Accessed August 14, 2013.
  111. Available at: http://www.westonaprice.org/metabolic-disorders/low-metabolic-energy-therapies. Accessed August 14, 2013.
  112. Burger HG, Hale GE, Dennerstein L, Robertson DM. Cycle and hormone changes during perimenopause: the key role of ovarian function. Menopause. 2008 Jul-Aug;15(4 Pt 1):603-12.
  113. Available at: http://www.businessweek.com/news/2012-06-19/pfizer-paid-896-million-in-prempro-accords-filing-shows. Accessed August 7, 2013.
  114. Available at: http://www.prempro.com/. Accessed August 14, 2013.
  115. Available at: http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm168838.htm. Accessed August 14, 2013.