Bio-identical Hormone Therapy; What

1
Bio-identical Hormone Therapy Whats the Real
Science ?

• Alan M. Altman, MD
• Harvard Medical School
• Brigham and Womens Hospital

2
Disclosure

• Advisory Board
• Solvay
• Novogyne
• Warner-Chilcott
• QuatRx
• Wyeth

• Speakers Bureau
• Solvay
• Novogyne
• Warner-Chilcott
• Ascend
• Esprit

3
Two Categories of Menopausal Symptoms

• Estrogen withdrawal
• Resolve with time
• Hot flashes
• Night sweats
• Sleeplessness
• Palpitations
• Headaches
• Mood swings
• Fatigue

• Estrogen deficiency
• Worsen with time
• Vagina
• Brain
• Bone
• Blood vessels
• Skin
• Joints
• Mucous membranes
• Genitalia

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HT RIP 2002
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WHI What the Investigators Concluded

• Health risks of conjugated equine estrogens (CEE)
  MPA exceeded benefits in population studied
• HT regimen (CEE MPA) tested in WHI did not
  promote primary prevention of chronic diseases
• CEE MPA regimen should therefore not be
  initiated or continued for primary prevention of
  CHD

Rossouw JE et al. JAMA. 2002288321-333.
6
WHI What Findings Do and Do Not Tell Us

• CEE-MPA
• Not preventive of cardiovascular disease in late
  menopause
• Increased incidence of thrombotic/ischemic stroke
  (after 2 years)
• Decreased fractures, decreased colon cancer
  incidence
• Inconclusive about
• Preventive effects when CEE-MPA initiated in
  early menopause
• Oral HT other than CEE-MPA
• Effects of non-oral HT
• Effect of androgens

Rossouw JE et al. JAMA. 2002288321-333.
7
Unified Hypothesis Benefit of HT Versus Risk
Postmenopausal Hormone Therapy Critical
Reappraisal and a Unified Hypothesis Lawrence S.
Phillips, MD Robert D. Langer, MD. Fertility
and Sterility. 200583558-566. Must read for
all cliniciansespecially primary care physicians
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Hypothesis CHD Benefit and Risk with HT
No or local progestogen

Less risk
Initiation long after menopause
Initiation at menopause
Risk
Benefit
More risk

Systemic progestogen
Adapted from Phillips LS, Langer RD. Fertil
Steril. 200583558-566.
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WHI EP Trial Time Since Menopause May Be Better
Than Age at Predicting CHD Risk With HT
Age (y)
5059
6069
7079
Years Since Menopause
lt10
1019
?20
1.27
1.05
1.44
0.89
1.22
1.71
HR for CHD
HR hazard ratio.The dotted vertical line
indicates the overall CHD odds ratio (1.24). P
values for interaction were not
significant. Manson JE, et al. N Engl J Med.
2003349523534. Evidence Level A
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WHI E-Alone Trial Trend Toward Cardioprotection
in Younger Menopausal Women
Age (y)
5059
6069
7079
HR
Data for time since menopause not available. P
.14 for interaction. Women's Health Initiative
Steering Committee. JAMA. 200429117011712
Evidence Level A Hsia J, et al. Arch Intern
Med. 2006166357365. Evidence Level A
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Vindication!
Data from postmenopausal women in the Nurses
Health Study, with follow-up from 1976 to
2000. Women beginning HT near menopause had a
significantly reduced risk of coronary heart
disease (RR0.66, 95 CI 0.54-0.80 for estrogen
alone RR0.72, 95 CI 0.56-0.92 for estrogen
with progestin.)
Grodstein F et al. J Womens Health. 20061535-44.
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HT Safer in Younger Menopausal Women?

• Recent meta-analysis, as well as the Nurses'
  Health Study update, suggest HT use by younger
  menopausal women reduces CHD risk
• WHI analysis of EP, CHD risk also suggested
  cardioprotection in women most recently
  menopausal
• These findings are reassuring regarding HT
  cardiovascular safety in younger women

Salpeter SR, et al. J Gen Int Med.
200419791-804 Evidence Level A Grodstein F,
Manson JE, Stampfer MJ. J Womens Health.
2006153544 Evidence Level C Manson JE, et
al. N Engl J Med. 2003349523-534. Evidence
Level A
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Hypothetical Sequence of Coronary Damage
No HT
MMP-9
Adventitia
FibrousCap
FibrousCap
Media
InternalElasticLamina
FibrousCap
Plaque
Plaque
Necrotic Core
Plaque
Necrotic Core
Fatty Streak/Plaque
HT Early Continued
HT
HT Late
Mural Thrombus
HT
35-45
45-55
55-65
gt65
Age (years)
15
5054 Year Age Group
Conservation Oophorectomy
Probability of survival to 80 62.46 53.88
Est. mortality rates by age 80 for Est. mortality rates by age 80 for
Hip fractures 3.38 (2.06) 4.96 (3.17)
Ovarian cancer 0.47 (same) 0 (same)
Breast cancer 1.82 (same) 1.77 (same)
Stroke 2.59 (3.60) 2.47 (3.59)
CHD 7.57 (same) 15.96 (7.56)
Parker,WH et al Clinical Ob Gyn
50(2)354-361 June 2007.
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Estrogen-Containing HT Is Neuroprotective in
Younger Women

• Primary prevention of neuron loss
• Reduced incidence of Alzheimer's with early
  intervention
• WHIMS Increased memory problems in older cohort
• MIRAGE Decreased memory problems in younger
  cohort

Hosoda T, et al. Neuroreport. 2001121965-1970
Honda K, et al. J Neurosci Res. 200164466-475
Henderson V, et al. J Neurol Neurosurg
Psychiatry. 200576103-105 Zandi P, et al.
JAMA. 20022882123-2129 Shumaker S, et al.
Control Clin Trials. 199819604-621.
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Lower Incidence of Alzheimers with HT in
Younger Women During Menopause
MIRAGE Trial Observational analysis of relation
between HT and AD in 971 postmenopausal women
0.97
0.86
0.70
Adjusted Odds Ratio
0.35
Adjusted for age, education, and ethnicity.
Henderson V et al. J Neurol Neurosurg
Psychiatry. 200576103-105.
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Depression, Estrogen and the WHI

• Within 2 mos. of the publication of WHI, women
  with a lengthy hx of depression, who had been in
  remission, began to have a reemergence of their
  depressive symptoms shortly after D/C HT
• Within 3 weeks of HT discontinuation
• Responded to reinstitution of estrogen, or
  initiation or increase in anti-depress. dose
• Discontinuation of HT appears to be assoc. with
  the rapid recurrence of depression in some women
  with a hx of depression.
• Stewart DE, et al Depression, Estrogen, and the
  WHI Psychosomatics 45445-447 October 2004

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No Increase in Breast Cancer Incidence with CEE
Alone for 7.1 Years
In Situ Breast Cancer
Invasive Breast Cancer
Total Breast Cancer
0.04 0.03 0.02 0.01 0
HR, 0.86 (95 CI, 0.51-1.46) Log-Rank P.58
HR, 0.80 (95 CI, 0.62-1.04) Log-Rank P.09
HR, 0.82 (95 CI, 0.65-1.04) Log-Rank P.10
Cumulative Hazard
0 1 2 3 4 5 6
7 8 9
0 1 2 3 4 5 6
7 8 9
0 1 2 3 4 5 6
7 8 9
Time, y
Time, y
Time, y
No. at Risk CEE 5310 5160
4989 4426 1357 484 5310
5165 5001 4444
1365 487 5310 5160 4989
4426 1357 484 Placebo 5429
5270 5081 4479 1443
603 5429 5429 5275
5097 4498 603 5429 5270
5081 4479 1443 603
Stefanick ML, et al. JAMA 20062951647-1657.
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Cohort Study of ET and EPT and Breast Cancer

• N 54,548 newly menopausal women (mean age 52.8
  y) mean duration of HT 2.8 y
• 948 Primary invasive breast cancers during mean
  follow-up (5.8 y)
• Risk ratios HT vs nonusers
• ET 1.1 (CI 0.81.6)
• EPT 1.3 (CI 1.11.5)
• ET/synthetic P 1.4 (CI 1.21.7)
• ET/micronized P 0.9 (CI 0.71.2)

Fournier A, et al. Int J Cancer.
2005114448454. Evidence Level B
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Unequal risks for breast cancer associated with
different progestagens

• The French E3N cohort study
• 1990-2002, mean follow-up 8.1 postMP years
• Estrogen alone RR 1.29 (1.02-1.65)
• E progesterone RR 1.00 (0.83-1.22)
• E dydrogesterone RR 1.16 (0.94- 1.43)
• E other progestagens (androgenic,
  non-androgenic, antiandrogenic) RR 1.69
  (1.50-1.91)
• Fournier, A et al. Breast Cancer Res Treat 2007
  DOI 10.1007/s10549-007-9523-x

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Tara Parker-Pope WSJJuly 9,2007

• But in the five years since, it's become clear
  that some aspects of what was initially reported
  from the 725 million Women's Health Initiative
  study were either misleading or just wrong.
• Last month, the New England Journal of Medicine
  reported that 50-59-year-old women in the WHI who
  regularly used estrogen alone showed a 60 lower
  risk for severe coronary artery calcium, an
  important risk factor for heart attack.

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WSJ, cont.

• Still, he ( J. Rossouw MD ) defends the
  government's handling of the study results "based
  on what we knew at the time," and says that study
  officials wanted to make a dramatic statement.
  "Our main job at the time was to turn around the
  prevailing notion that hormones would be useful
  for long-term prevention of heart disease," he
  says. "That was our objective. That was a worthy
  objective which we achieved."

24
Editorial Climacteric 2007, cont.

• estrogen-alone users, who were 80 or more
  compliant, had 61 less atherosclerotic plaques
  in women whose mean age was 55 years at baseline,
  as compared to a placebo group (p 0.004).

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WHI-CACS Hodis review

• WHI-CACS Women who initiate ET in close
  proximity to MP have reduced coronary artery
  atherosclerotic heart disease.
• Effect was greatest in women who were the most
  compliant with Rx
• This effect was unequivocal and consistent with
  the large body of evidence that ET reduces
  atherosclerosis, CVD, and total mortality in
  women less than age 60.
• Hodis HN, Mack WJ. Postmenopausal hormone therapy
  in clinical perspective. Menopause 2007141-14

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WHI less than 60yo who initiate ET
Clinical event Percent reduct. per 10,000 w
CHD 37 11
Stroke 11 2
New onset DM 12 14
Bone fractures 30 56
Breast cancer 18 8
Total mortality 29 10
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Howard Hodis MD Menopause2007, cont.

• The assumption made by the WHI investigators
  that initiating HT in young women in close
  proximity to menopause could result in increased
  risk as women age is completely unsubstantiated
  and, in fact, contradicts the literature.
• all available evidence indicates...quite the
  opposite the earlier prevention is initiated,
  the greater the long-term benefit.

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• Estrogen
• Progestin

29

• Oral vs Non-oral Estrogen use
• The real bio-identical
• hormones

30
Oral HT Induces Hepatic Enzymes via First-pass
Effect
GeneralSystemicCirculation
Liver
PortalVein
Minkin MJ. J Reprod Med. 200449311-320.
31
Transdermal HT Avoids First-pass Induction of
Hepatic Enzymes
GeneralSystemicCirculation
Skin

• No first-pass metabolism
• More stable circulating levels
• Improved lipid and clotting profile

Adapted from Minkin MJ. J Reprod Med.
200449311-320.
32
Effects of First-pass Hepatic Metabolism
Oral Estrogen Non-Oral Estrogen
First-pass metabolism Yes No
Lipid effects
HDL-C ? or generally unchanged Slight ? or ?, or unchanged
Triglycerides ? Significantly ? Significantly
LDL-C ? ?
Total cholesterol ? ?
SHBG ? x
Clotting factors ? x
Thyroid binding globulin ? x
Glucose ? x
Insulin resistance ? x
C-reactive protein ? x
Renin substrate ? x
Estroneestradiol ratio ? x
x No clinically significant effects
Minkin MJ. J Reprod Med. 200449311-320.
33
Oral and Non-oral EstrogenEffects on Lipid
Profile
Meta-analysis of Prospective Studies (1974-2000)
Oral CEE 0.625 mg/d (46 studies) Oral estradiol
1.0 mg/d (5 studies) Transdermal estradiol 0.05
mg/d (19 studies)
18.6
14.8
13.4
8.7
5.1
Change From Baseline ()
Total Cholesterol
LDL-C
HDL-C
-0.8
-2.6
-3.3
-3.9
-5.0
-8.6
Triglycerides
-11.7
Godsland IF. Fertil Steril. 200175898-915.
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Physical State of Testosteronein Plasma
19 Albumin-bound Testosterone
1 Free Testosterone
80 SHBG-bound Testosterone
Vermeulen A, et al. J Endocrinol Metab.
1969291470-1480.
35
SHBG

• Binds T preferentially, but also E
• Only free hormone affects receptors
• Oral estrogens increase SHBG
• Androgen relative deficiency
• Estrogen symptom relapse
• Oral androgens decrease SHBG
• Non-oral estrogen does not increase SHBG

36
SHBG (nmol/L) Free T (pmol/L)
Vehkavaara S,et.al.Circulation2000
37
Methyl testosterone and sexuality

• Comparative effects of oral EE with and without
  MT on endocrine profiles dimensions of sexual
  function in post menopausal women with hypoactive
  sexual desire.
• significantly improved sexual functioning in
  women receiving the combination of EE and MT.
• Lobo Rosen, et al. FertilSteril 2003 79
  1341-1352

38
EE/MT and endocrine profiles

• A significant (plt.010) decrease of SHBG occurred
  in patients receiving combination Rx.
• The mean serum concentration of bio-available T
  significantly increased ( approx. doubling ) in
  patients receiving combination Rx (plt.010)
• Lobo Rosen

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WHI Results Summary of CVD Outcomes
Outcome HRT No.() Placebo No.() Hazard Ratio Nominal 95 CI Adjusted 95 CI
CHD 164(0.37) 122(0.30) 1.29 1.02-1.63 0.85-1.97
CABG/PCTA 183(0.42) 171(0.41) 1.04 0.84-1.28 0.71-1.51
Stroke 127(0.29) 85(0.21) 1.41 1.07-1.85 0.86-2.31
VTE 151(0.34) 67(0.16) 2.11 1.58-2.82 1.26-3.55
Total CVD 394(1.57) 546(1.32) 1.22 1.09-1.36 1.00-1.49
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EStrogen THromboEmbolism Risk Study Group
ESTHER

• Current users of oral ERT seem to be at higher
  risk of VTE than users of transdermal ERT. There
  was no association between VTE risk and the use
  of transdermal ERT.
• VTE risk was highest in the first year of oral
  ERT use, which is consistent with previous data.
• Scarabin PY, et al. ESTHER, Lancet 2003 362
  428-32

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Odds ratio of VTE in relation to ERT use

• Relative to never users
• current oral 3.9 ( 2.0-7.6 )
• current t-dermal 1.0 ( 0.5-1.7 )
• Relative to non-users
• current oral 3.5 ( 1.8-6.8 )
• current t-dermal 0.9 ( 0.5-1.6 )
• Relative to current users of t-dermal
• current t-dermal 1.0
• current oral 4.0 ( 1.9-8.3 )
• ESTHER

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ESTHER StudyEstrogen Use and VTE Risk
Risk of VTE

• Multicenter, hospital-based, case-control
  observational study
• France 1999-2002
• First episode VTE (n 155)
• Pulmonary emboli (n 92)
• Deep venous thrombosis (n 63)
• Controls (n 381)
• Matched for center, age, and time of recruitment
• Estrogen
• Oral (estradiol)
• Transdermal
• Gel (56) or patch (44)

3.5 (1.8-6.8)
Adjusted Odds Ratio (95 CI)
0.9 (0.5-1.6)
1.0
Oral Transdermal Nonusers ERT Use ERT Use (n
93) (n 32) (n 30)
Adjusted for BMI, familial history of VTE,
history of varicose veins, and educational level.
Scarabin P-Y, et al. Lancet. 2003362428-432.
43
ESTHER w/ prior VTE and mutationStraczek C, et
al. Circulation 2005112(22)3495-500
Group HR (RR) CI
Non-user 1.0 --------
TDE (w/o mutation) 1.2 (0.8-1.8)
Oral (w/o mutation) 4.1 (2.4-7.1)
Non-user (w/ mutation) 4.1 (2.3-7.4)
TDE (w/ mutation) 4.4 (2.0-9.9)
Oral (w/ mutation) 25.5 (6.9-95.0)
44
ESTHER Study Hormone therapy and DVT among
postmenopausal women

• For estrogens,
• Oral, 4.2
• Transdermal, 0.9
• For progestins,
• DVT vs non-users
• Micronized 0.7
• pregnane derivatives, 0.9
• non-pregnane derivatives, 4.0

Canonico M et al. Estrogen and Thromboembolism
Risk (ESTHER) Study Group Hormone therapy and
venous thrombosis among postmenopausal women
impact of the route of estrogen administration
and progestogens the ESTHER study. Circulation.
2007 Feb 20115(7)840-5.
45
C- reactive protein CRP

• Strong predictor of cardiovascular events plaque
  fracture, thrombosis
• Both a marker (and a mediator) of CHD risk
• Enhances inflammation and promotes tissue damage
  in acute myocardial infarction
• Non-oral estrogen does not increase CRP as oral
  does

46
Effect of Oral Versus Transdermal Estrogens on
hs-CRP Levels
Median hs-CRP, µg/mL (interquartile range)
Baseline
(0.625 mg/d)
Control
(0.10 mg/d)
Vongpatanasin W, et al. J Am Coll Cardiol.
2003411358-1363.
47
Estrone Estradiol Ratio (E1E2)
Plasma Breast and adipose tissue
Pre-menopausal 1 1 - 2
Non-oral E 1 0.5 - 2
Oral E 3 - 5 20
48
Breast Density Transdermal vs Oral
Transdermal () Transdermal () Oral () Oral ()
Mean adjusted breast density Mean adjusted breast density 38.4 38.4 46.9
Marked increase in breast density gt25 increase Marked increase in breast density gt25 increase 4 4 15.7
No increase at all No increase at all 39.1 39.1 15.7
Breast tenderness Breast tenderness 36.0 36.0 57.6
Harvey J, et al. Climacteric. 20058185192.
49
Vasomotor symptomatology

• Not due to low levels of estrogen
• Due to estrogen withdrawal
• Oral estrogen intake peaks and valleys
  estradiolCEE
• Non-oral estrogen more stable levels withdrawal
  rare weekly vs bi-weekly patches

50
Estrogen Levels Oral vs Transdermal Patch ET
Nonbaseline-Corrected Levels
Estrogen Levels
120
200
Twice-per-Week Patch1
Transdermal vs Oral2
100
150
80
60
100
E2 Serum Level (pg/mL)
E2 Serum Level (pg/mL)
40
50
20
0
0
13
14
1
2
3
4
11
12
Time (d)
Time (d)
Oral Micronized E2 (2.0 mg/d) Percutaneous
E2 (gel, 80 mg/d) TE (50 mg/d)
Transdermal E2 (TE) 0.075 mg/d TE 0.0375 mg/d
1. Vivelle-Dot Prescribing Information. East
Hanover, NJ Novartis Pharmaceuticals Corp. 2005
2. Scott RT Jr, et al. Obstet Gynecol.
199177758764.
51
Non-oral estrogen options

• Transdermal
• patches
• gel
• creams pharmaceutical vs compounded
• Transvaginal
• rings local vs systemic
• tablets
• creams
• Parenteral
• (contra)

52
Considerations for Non-oral Therapy

• Non-oral regimens may have particular advantages
  for women with
• Preference for non-oral therapy or non-daily
  therapy
• Symptoms that do not respond to oral therapy
• Elevated triglycerides1
• Type 2 diabetes1
• Sexual dysfunction2
• Migraine headaches1
• Depressive symptoms3
• Smokers1
• Gallbladder disease1
• Hypertension1
• Gastrointestinal disturbances1

1. Nachtigall LE. Am J Obstet Gynecol.
1995173(3)993997. 2. Campagnoli C, et al.
Gynecol Endocrinol. 19937251258. 3. Soares CN,
et al. Arch Gen Psychiatry. 200158529534.
53
Oral, Non-oral HT Options Have Different
Contraindications
Absolute

• Unexplained vaginal bleeding
• Pregnancy
• Temporary contraindications
• History of breast cancer or endometrial cancer
• With precautions, short-term use of hormone
  therapy may be considered for women with severe
  symptoms

• History of hormone-induced thromboembolism
• History of pulmonary embolism not caused by
  trauma
• Severe hypertriglyceridemia
• Endometriosis

Contraindications for oral estrogens only
Relative

• Chronic liver disease

Institute for Clinical Systems Improvement.
October 2004. Available at http//www.guidelines.
gov/summary/summary.aspx?ss15doc_id6146nbr397
4. Accessed March 29, 2005.
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Words

• Natural
• Synthetic
• Bio-identical

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Recent authoritative text

• Suzanne Sommers
• Bioidentical hormones vs. pharmaceutical hormones
• one-size-fits-all
• synthetic
• blood levels
• Breast cancer risk and what is implied by this
  book

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A question of growing importance

• Who is the asymptomatic post-menopausal woman
  and where can we find her ?