Bioidentical Hormones - U.S. Senate Special Committee on Aging

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CEE did 'tot significantly affect total mortality rates or cause-specihic mtortality (TABLE 4). Time Trends Differences in cumulaive hazards for stroke and lo a lesser extent [or hip fracture began to emerge early in the intervention period and persisted throughout follow-up (FiGtttE 3). Cumulative breast cancer hazard rates appeared to separate begittning in year 2. Similar dlisplays for the global index and death (FlriGiR 4) reinforce the comparability of these rates across treatment groups. Tests for trends with time since 175 randomization were computed for all of the monitored and composite outcomes using a Cox proportional hazards model with a time-dependent treatment interaction term. Coronary heart disease was the only outcome with a statistically significant trend (P=.02) of slightly elevated HRs in the early follow-up period that dimiuished over lime (year 1.1.16: year 2,1.20; year 3, 0.89, year 4. 0.79; year 5,1.28; year 6, 1.24, and year 27, 0.42). Further Analyses Exploratory analyses were conducted to determine whether selected partci- Figure 3. Kaplan-Meier Estimates of Cumulative Hazards for Selected Clinical Outcomes Cornmary Hean4 Disease 005 HR 0 9 (9 05', % C,tO .1 0,,2 i2 002' ouot ll, Eow 02 00 3t 00 0' 00 1 7 s ruow tO 00 05 05 z 25 00 tO t7 N3 .. R~ ane Otto s2-O 0147 trot7 rot Osr 300 0040 ors rOeC rote 5WID 5254 5 500 4026 4010 z0 114e 50001. Breast Carneo 05%e 0. 0.50.1.011 705.SD 002 ren. Y Er OM 9 11 13 17 10 1O 0 o 5 r 3. *s 2 z- 4 z , s Io N.10 20k rEt 5310 5s zst 'sot 0000 4am 33s7 2271 loll ro 0 1 25100 .00 4050 4057 0300 7110 1 HRI 3 J 89%Stt Stroke ii 70. 15 *7 00 30 10 0 3 r S' 2 z2 'no z- o5 2100 213 51t 525 iSlte 003 rD i 00 01 srt 1 500- 500 sar 000 -6* 00,0 1710 HR t.0 56% 0, 0.7 05. 51 Colorectal Coreer 0 I 2 3 4 5 5 1 e Trose. y 1 l o lo e 1 s 3 21 I I .0 0 5 3 2 0310 S2W7 515005l ton 009 4 ml 0005 1027 s MI WIa SINa s-ss Soro sm2 1 2e 36Q II EFFECTS OF POSTMENOPAUSAL ESTROGEN pant characteristics modified CEE effects on major clinical outconte event rates. There were no significant interactions between CEE and race/ Table 4. C-ases of Death No. Annuaoned %l rotaldeoths Aduidairced deots CEE Placebo (0 s5310) (n s 5429) 2911(081) 289)0.78) 278 (0.77) 272 (0.73) CaGcovasular 93 (0.26) 5 (0.26) Breat caower Otth cwase, 4 (0.01) 110 (030 8 (0.02) 118 (0.32) Oltherokncawer 51(0.14) 38(0.10) tUnk cause 20 (0.05) 13 (004) AbbE-ioas. aEE, cos-Ar,9.I 01e,0-o5r0n. Pulmtonary Eroitotisro 5% bi 3~ ow, t w MI 52 -Su, .OD A . iolo root ts7m on,7 smoo ro 3m~ z20s2 020 5400 5302 tOM 52-s 5-17 020400e 2050r123 Hip Froatur 'tost o6 95% 0.001.0ol I i 2 3 4 s t 7 8 r l . n It 5010 5033 5171 SIM2 03 020 ion0000 1010O! 5000 s20. 570 s- oo 10 4ro oro 0070 t1o- CEE odicue coe-ugated eqNoe Hstmeee h.aad rado, Cl, corfidenta ntOevl Eventr sh-mnare orcudng dunng l ynr intemais through yt-r 8 0nd beyond yrar 8. 0120-1) Altncrir INIIrdic3l A*s1iontll. All righlt, rcsr cd. (Rlitpied) JAM, Apnl Ii, !0D-Vol 231, 14 1707 Dtmonlsoaded from v.joa.-coin a0 Natinnat tituteof lilh, on Apnil 16. 2007
pEyECTS OF POSTMENOPAUSAL ESTROGEN 176 Figure 4. Kaplan-Meier Estimates of Cumulative Hazards forCoba1 Inde. and Death Gloal Ind 0 20 HR 0 05*0 00.2 22 D.eah HRisi 5%c0N0-l 23 C [ IJ 015 0 0 1 2 3 5 G 7 a Ev~~~~~~~~~~~r cc82 as7 48 6 13 51 , 21 FOX e; rim r 36 es WaS us tO rs a 1 2 3 a5 6 7 a y 2. 4 23 3252 so 4611 w- Ia 25 432364a62362? CPE 5317 5 'WI 274 21 3 Po 52 000 5244 403 .620 475 3166 2264 NU 2 saC SO7 52 12 tea 465 2025 2fe1026 5=220 535 5250 5223 1 5 4092 23 s1a CEE indicate conjugated equine estrogen, HR, hazard rgoa Cl. confidence iet-rvaf Eents sea are occurnng durng I yr.r ntervai th-gofh yea, 6 and beyond year 0 etinicity or body mass index on risk of CHD, stroke, VTE. breast cancer, co- Sensitivity analyses were conducted to provide an indication of the potenlorcctal cancer, hip fracture, or total ostial impact of lack of adherence to asteoporotic fracture (data not shown). signed study medication. Compared Of particular interest for all outcomes with the primary iment-to-treat analy- was age at enrollment (FIGURE 5). The only treatment x age interaction reachses (Table 3), the 'complier' models estimated greater risks of stroke (HR, ing statistical significance was for 1.74), pulmonary embolism (HIR, 1.99), colorectal cancer (P= .048), for which increasing age was associated with in- and total mortality (HIR, 1.26) hut low. er risks of breast cancer (HR, 0.65), hip creasing risk with CEE use. The effect of prior disease on car- fracture (HR, 0.48). and colorectal cancer (HR, 0.92). The HRs for CHD (HR, diovascular event rates svas also evaluated. Among the 441 women enrolled 0.89) and the global index (HR, 1.06) were essentially unchanged. vith prior Ml or renascularization procedures, the effect of CEE relative COMMENT to placebo (33 vs 31: HR, 1.04; 95% The WHI estrogen-alone study was Cl, 0.63-1.71) did not differ signifi- a large-scale, randomized, doublecantly from the CEE effect in women wsithout documented CHD (143 vs blind, placebo-controlled trial designed to test the effects of the most 162; HR, 0.91; 95% Cl, 0.73-1.14) commonly used postmenopausal hor- (P=.55). Similarly, in 168 women reporting prior stroke, the HR for subsequent stroke (6 ss 6: HR, 1.67; 95% mone therapy preparation in the United States" Cl. 0.52-5.36) did not diller from the HR in women without a history of stroke (152 vs 112: HR, 1 39; 95% Cl, 1.09-1.78) (P=.77). Removing from analysis the few participants with a history of PE did not alter the hazard ratio for PE substantially (47 vs 37; HR, 1.31, 95% Cl, 0.85-2.01). 6 CEE increases the risk of stroke, reduces the risk of hip and other fractures, but does not significantly affect the incidence of CHD (the primary outcome) or overall mortality. A nonsignificant reduction in breast cancer incidence requires additional irwestigafion. These observed risks and benefits of CEE for chronic disease rates appear to be balanced over an average 6.8-year follow-up period. The lack of effect of CEE on CHD risk is substantially different from the favorable reports from observational studiesthat nmotivated this trial, and was observed despite an improvement in cholesterol levels. However, these resulis are consistent with several recent secondary prevention trials that showed no benefit of hormone therapy on atherosclerosis or clinical events."' on chronic disease incidence in a diverse population of mostly healthy postmenopausal women aged 50 to 79 years. As conceived, the study had adequate power to detect moderate effects on CHD; hip fractures, and with longer-term follow-up, breast cancer among women across the broad age range relevant for disease prevention hypotheses. This trial demonstrated that 1 The current study suggests that youinger women who use CEE may be at reduced risk of CHD but this possible association may be due to chance. These CHD results for CEE also differ importantily frotn 2 previous trials of estrogen plus progestin. In both the WHI estrogen plus progestin trial]2 and HERS, 26 the risk of CHD was significantly elevated in the first year of treatment and the cumulative effects of estrogen plus progestin never appeared beneficial. In the current study, a smaller, nonsignificant increase was observed in the first year of CEE exposure but the cumulative effect suggests a possible modest benefii with longer-term use. Potential explanations for this discrepancy include the role of progestin, differences in the study populations in baseline risk factors,' 0 duration of intervention and follow-up time, and the role of chance. The observed adverse effect of CEE on the risk of stroke is consistent with the risks reported by the WHI and HERS estrogen plus progestin trials." 27 In addition, the use ofesuadiol in women after ischemic stroke resulted in no change in mortality but a higher rate of recurrent nonfatal stroke and a suggestion of more severe functional deficits_24 The small but persistent increase in systolic 1708 )AM& ApnI 14. 2004-V.1 291. N.. 14 (11qitd) 2708 p . Apa t talnha Medical -ialt.on. All rig)-i iiuis.d.
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S. HRG. 110-129 Bioidentica
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CONTENTS Page Opening Statement of
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2 The sale of bioidentical hormone
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4 ever, as Dr. Wartofsky points out
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6 with every stage of the disease:
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8 I am pleased to appear before thi
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10 When the trials began, many rese
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Women who began treatment more than
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14 One small trial using oral estra
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16 FDA is aware that a growing numb
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18 DEPARTMENT OF HEALTH & HUMAN SER
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20 safety and efficacy. However, as
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22 adulteration and misbranding pro
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24 The 2002 CPG reflects FDA's curr
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26 Equally concerning are claims by
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28 concerned about the use and mark
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30 Part I: Materials and Partnershi
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32 drugs, when the compounding of t
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34 Our staff identified 34 Web site
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1. Introduction 36 Chairman Kohl, R
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diet and fitness products. 5 For ex
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include "natural" progesterone crea
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42 unique to the computer age, such
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computer users to spam(ftuce.0ov -
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46 accuracy of advertising for heal
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48 Now, you have identified in your
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50 claim." Therefore, since the ter
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52 Such quality control problems ha
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54 Statement Before the U.S. <stron
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in the U.S., whereas WHI participan
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58 between science and hearsay and
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60 How can we determine whether bio
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62 doctors-are not getting the obje
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64 27. Writing Group for the PEPI T
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66 Dr. MANSON. Well, I think that m
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68 Statement of Leonard Wartofsky,
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70 in the WHI. In fact, no study as
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In summary, the Endocrine Society i
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74 The FDA also regulates aspects o
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Statement of Loyd V. Allen, Jr., Ph
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82 Senator SMITH. Dr. Allen, as I h
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84 Now, when you are talking about
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86 The only thing the WHI proved wa
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88 Testimony Of T.S. Wiley before t
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Confusion and Media Hype 90 Instead
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92 see a doctor tell a diabetic nea
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94 the only compelling reason to ta
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96 identical hormones synthesized f
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98 The world as we know it, from ba
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100 thereby experienced long period
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102 Bio-identical progesterone repl
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104 had reached optimum theoretical
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106 and the patient can be can reas
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108 Estradiol and Analytical Resear
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110 A controlled systematic pilot c
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112 of set doses. The Wiley Protoco
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114 I'd advocate for either Accredi
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116 D.C., and established a goal to
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118 If this legislation passes, fed
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first and second finger on the barr
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122 These products that have been s
Page 127 and 128: 124 Bcl-2, survivin and variant CD4
Page 129 and 130: 126 These are experiments by other
Page 131 and 132: 128 cerebro-cellular inflammation c
Page 133 and 134: 130 Years # women *1>0.5 8 *1+ 9 *2
Page 135 and 136: *Breast cancer 132 -57 y.o. recurre
Page 137 and 138: 134 *Labor intense for patient and
Page 139 and 140: 136 Senator SMITH. Thank you very m
Page 141 and 142: 138 makes these hormones uniquely s
Page 143 and 144: 140 tomize the Wiley Protocol by ra
Page 145 and 146: 142 "natural," because all lead to
Page 147 and 148: 144 maceutical commerce, often with
Page 149 and 150: 146 WHITE PAPER #1 DID YOU KNOW THA
Page 151 and 152: 148 WHITE PAPER #2 Pharmacy Compoun
Page 153 and 154: 150 bleeding of the bowel, locate t
Page 155 and 156: 152 compounding standards can be en
Page 157 and 158: 154 I. The FDA's definition of a "N
Page 159 and 160: 156 ORIIGINAL CONTrMIBTION JANMA-EX
Page 161 and 162: Initially, the design allowed women
Page 163 and 164: ards analyses," stratified by clini
Page 165 and 166: year). These 'drop-in" rates were a
Page 167 and 168: years of prior use, 11 vs 2; HR, 4.
Page 169 and 170: trogen plus progestin exposure. Clo
Page 171 and 172: 168 RISKS AND BENEFITS OF ESTROGEN
Page 173 and 174: EFFECTS OF POSTMENOPAUSAL ESTIROGEN
Page 175 and 176: EFFECTS OF POSTMENOPAUSAL ESTROGEN
Page 177: EFFECTS OF POSTMENOPAUSAL ESTROGEN
Page 185 and 186: 10000 isoor i I ea '° a wan 20-24
Page 187 and 188: ~SDt~rpa g~2~Q ~ !~fm~. b~e ~ ng jh
Page 189 and 190: Is associated with an Increased ris
Page 191 and 192: 188 Postmenopausal hormone therapy
Page 193 and 194: group (P= 04001), and In this subgr
Page 195 and 196: Treatmnent recommendations Based on
Page 197 and 198: 21.Grodsteln F. Manson JE, Colditz
Page 199 and 200: _ ORWIGNAL CONTIuBUTION 196 Postmen
Page 201 and 202: showed no striking differences in H
Page 203 and 204: (214 cases; P for trend=.72): howev
Page 205 and 206: 202 HORMONE THERAPY USE AND RISK OF
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Page 213 and 214: 210 ,lmcCII na: CLI I tr: tarty ver
Page 215 and 216: 212 ,mucmai rimi &ronos farty bstro
Page 217 and 218: 214 LntIucwu miau: rronos nary estr
Page 219 and 220: XVI. PNharmacy Licensure Requiremen
Page 221 and 222: XVI. Pharmacy Licensure Requirement
Page 223 and 224: 220 Roster of Board of Pharmacy Ece
Page 225 and 226: 050. 0l7404405400 Al-h. PeVbU 03283
Page 227 and 228: Conclusions * Age is a powerful ris
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Women's Health Initiative Trials of
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Hormone Therapy after WHI * Change
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Statement of the American Pharmacis
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232 APhA Statement to the S
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240 Written Testimony of Steven F.
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242 STATEMENT OF DAVID G. ADAMS On
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244 Report on State Laws and Regula
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246 Only one state, Utah, requires
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248 5. Compounding Copies of FDA-Ap
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