(Un

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(Unübliches zur) Menopause
Bruno Müller

• www.DerEndokrinologe.ch
• Bern

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Absturz / Pause oder Abflug?

• Machen Sie sich selber ein Bild

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Der Temperaturanstieg um ca. 0,6 C ist ein
Gestageneffekt
Östrogene Proliferation, Zervikalsekret spinn-
bar, hoher Karyopyknose-Index
Gestagene sekretorische Umwandlung,
Vorbereitung Nidation/Eitransport
Zervikalsekret zähflüssig, niedriger
Karyopyknose-Index
Proliferative / Sekretorische Phase
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Pause / Abbruch oder Abflug?

• Endokrinologisch gesehen ist die Frau überaus
  komplex gesteuert .
• Leider sind Störfälle
• Oder gar definitive Funktionsausfälle
  vorprogrammiert ? Absturz

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Inhalte key points

• Menopause allgemein
• - Altern
• - Epidemiologie
• - Reparaturmechanismen

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• Alle versuchen, die Zeit totzuschlagen, und
  keiner will sterben
• Franz. Sprichwort

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Altern wir, weil die Menge wichtiger Hormone
abnimmt?
Oder nimmt die Hormonkonzentration ab, weil wir
altern?
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Nun sag, wie hast dus mit der Religion?
Die berühmte Gretchenfrage!
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Altern, am Bsp. der Oocyten

• 5th SS-Monat 7 million
• Geburt 1-2 Millionen
• Pubertät 400,000
• 40 -- Rascher Oocytenverlust

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Epidemiologie
Geburt Lebens- Erwartung Dauer der Menopause
1850 45 0
1900 50 0
1950 70 19
1960 73 22
1970 75 24
1980 79 28
1990 80 30
2000 80 30

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Demografische Angaben
Quelle Statistisches Bundesamt, Statistisches
Jahrbuch 2007
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Theories of Aging

• Genetic
• Aging is programmed into the genes
• Certain genes are timekeepers for the aging
  process
• Wear and Tear
• Cumulative damage to cells from
• Metabolic processes
• Environmental factors
• Mechanisms to resist and repair damage are
  critical

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Mechanisms to resist and repair damage

• Zelluläre
• Endokrinologische
• Lifestyle, Therapeutische (Hormonersatz, HRT,
  Alternatives)

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Cellular Damage and Defense
N
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Mechanisms to resist and repair damage

• Zelluläre
• Endokrinologische
• Lifestyle, Therapeutische (Hormonersatz, HRT,
  Alternatives)

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MenopauseSympome infolge Östrogen-Ausfall und
-Entzug

• Klimakterische Beschwerden
• Schweißausbrüche Müdigkeit
• Schlaflosigkeit Nervosität
• Herzrasen Depressive Verstimmungen
• Urogenitale Atrophie
• Atrophische Veränderungen des Harntrakts und ihre
  Folgen (z.B. vaginale Trockenheit, Dyspareunie,
  häufiges Wasserlassen und Harndrang)

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• Wenn uns Verzweiflung überkommt, liegt das
  gewöhnlich daran, dass wir zu viel an die
  Vergangenheit und an die Zukunft denken
• Hl Therese von Lisieux

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• Östrogen-Ausfall und/oder Entzug
• Stress
• Wie reagiert das Hormonsystem?

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SUMMARY OF HORMONE PHYSIOLOGY
Higher Centers
Neural activity (neurotransmitters)
-

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SUMMARY OF HORMONE PHYSIOLOGY
Higher Centers
Neural activity (neurotransmitters)
T4 80
T3 20 aktives Hormon
Konversion zu T3 peripher
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Control of androgen secretion
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(physischer) Stress und endokrines System,
Zusammenfassung

• (physischer) Stress führt zu
• Arousal der CRF-HPA-Achse
• vermehrter Cortisol-Produktion
• sekundärem Abfall von Testosteron (und Östradiol,
  Anstieg von Prolaktin, nicht gezeigt)
• und Wachstumshormon
• Verminderter Produktion (d. Konversion) von
  aktivem Schilddrüsen-Hormon T3

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• Östrogen-Ausfall und/oder Entzug
• Wie reagiert der Körper (body composition)?

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Age-related Changes in Body Composition and
Function
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Age-related Changes in Body Composition and
Function

• Body Composition
• Loss of lean body (muscle) mass
• Decreased strength
• Decreased fitness and loss of functional capacity
• Increase in total fat mass (percent body fat)
• Insulin resistance (type 2 diabetes)
• Increased LDL cholesterol, triglycerides, and
  fatty acids
• Decreased bone density (negative calcium balance)
  
• Metabolic/Physiologic Function
• Decreased protein synthesis
• Slower healing
• Reduced immune system function
• Altered hormone balance

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Age-related Changes in Body Composition in
Normal Sedentary Men
Muscle Mass (lbs)
70
Fat ()
60
50
Body Composition
40
30
20
10
20
30
40
50
60
70
80
Age (years)
(Balagopal et al. Endocrine 757, 1997)
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Decreases in Muscle Strength with Age
Men
250
Women
200
Isokinetic Force (Nm)
150
100
10
20
30
40
50
60
70
80
Age (years)
(Borges, Scand J Rehabil Med 2145, 1989)
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Altern wir, weil die Menge wichtiger Hormone
abnimmt?
Oder nimmt die Hormonkonzentration ab, weil wir
altern?
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How Do Hormones Change with Normal Aging?

• Estrogens- decrease to very low levels over a 1-3
  year period at menopause (between ages 45-55)
• Testosterone (T)- Gradual decline from age 30
  onward reaching low (hypogonadal) levels in gt20
  of men by age 65
• Growth Hormone (GH)- Gradual decrease in
  secretion (and circulating IGF-I levels) from age
  45-90

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How Do Hormones Change with Normal Aging?

• Adrenal Steroids-
• Active adrenal hormones (cortisol and
  aldosterone) change little
• DHEA, steady decrease with age to very low levels
  in both sexes
• Thyroid- not much change in healthy men and
  women, but increased prevalence of hypothyroid
  disease in older persons.
• Insulin- loss of sensitivity to insulin action
  with aging and obesity

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Mechanisms to resist and repair damage

• Zelluläre
• Endokrinologische
• Lifestyle, Therapeutische (Hormonersatz, HRT,
  Alternatives)

42

• Wichtigste Lifestyle-Massnahme
• Wer die Nacht nicht ehrt, ist des Tages nicht
  wert
• Italienisches Sprichwort

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Effects of Aging on Growth Hormone Secretion in
Men
15
Young
10
5
0
Growth Hormone (ng/ml)
800 am
1200 pm
400 pm
800 pm
1200 am
400 am
800 am
Time
(Corpas, et al., J Clin Endocrinol Metab 75530,
1992)
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• Gibt es sonst was zu tun, ausser viel schlafen?
• Müllersche Frage

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The International Menopause Society

• The IMS Updated Recommendationson postmenopausal
  hormone therapy
• February 27, 2007
• Climacteric 20071018194

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Exercise in themenopause

• Any physical activity is better than being
  sedentary
• Regular exercise reduces total and cardiovascular
  mortality
• Better metabolic profile, balance, muscle
  strength, cognition and quality of life are
  observed in physically active persons. Heart
  events, stroke, fractures and breast cancer are
  significantly less frequent
• Benefits far outweigh possible adverse
  consequences the more the better, but too much
  may cause harm

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Exercise in themenopause optimal exercise
prescription

• At least 30 minutes of moderate intensity
  exercise, at least three times weekly
• Two additional weekly training sessions of
  resistance exercise may provide further benefit

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AHA 2006 Diet and Lifestyle Recommendations 1

• Balance calorie intake and physical activity to
  achieve or maintain a healthy body weight
• Consume a diet rich in vegetables and fruits
• Choose whole-grain, high-fiber foods
• Consume fish, especially oily fish, at least
  twice a week

Circulation 200611482
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AHA 2006 Diet and Lifestyle Recommendations 2

• Limit intake of saturated fat to lt 7 of energy,
  trans fat to lt 1 and cholesterol to lt 300 mg/day
  by choosing lean meats and vegetable
  alternatives, selecting fat-free, 1 fat and
  low-fat products
• Choose and prepare foods with little or no salt
• Increase fiber intake (beans, whole grain, other
  fruits and vegetables)
• If you consume alcohol, do so in moderation
• Quit smoking

Circulation 200611482
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Mechanisms to resist and repair damage

• Zelluläre
• Endokrinologische
• Lifestyle, Therapeutische (Hormonersatz, HRT,
  Alternatives)

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Indikationen für eine HRT

• Klimakterische Beschwerden
• Schweißausbrüche Müdigkeit
• Schlaflosigkeit Nervosität
• Herzrasen Depressive Verstimmungen
• Urogenitale Atrophie
• Atrophische Veränderungen des Harntrakts und ihre
  Folgen (z.B. vaginale Trockenheit, Dyspareunie,
  häufiges Wasserlassen und Harndrang)
• Topische niedrig dosierte Präparate sind die
  Behandlung der Wahl, wenn lediglich lokale
  Beschwerden auftreten.
• Die Therapie klimakterischer Beschwerden erhält
  die Lebensqualität

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Praktische Empfehlungen zur Hormonersatztherapie
in der Peri- und Postmenopause
Menopausale EinschätzungSymptome
(Hitzewallungen, Schweißausbrüche,
Schlaflosigkeit, Müdigkeit, Reizbarkeit,
Nervosität, depressive Verstimmungen,
Urogenitalatrophie), körperliche Untersuchung
(Gewicht, Knochendichte), persönliche und
Familienanamnese, Risiko/Nutzen-Analyse
(Osteoporose, tiefe Venenthrombose, Brustkrebs,
koronare Herzerkrankung)
Symptome, aber HRT kontraindiziert
Nur urogenitale Atrophie
Menopausale Symptome
Erhöhtes Osteoporoserisiko/Frakturen bei
asymptomatischen Frauen

• Möglich sind
• Phytoestrogene
• a-adrenerge Agonisten
• Hoch dosierte Gestagene
• Selektive Serotonin-Wiederaufnahmehemmer (SSRI)
• Gabapentin

• Muskelaufbautraining
• nicht rauchen
• Calcium/Vitamin D
• HRT als erste Option
• Gefolgt von SERM und/oder Bisphosphonat und
  Teriparatid

Kein Uterus
intakter Uterus
Peri-meno-pausal
Post-meno-pausal
Topisches niedrig dosiertes vaginales
Estrogen
Niedrig dosierte Estrogenmonotherapie
Niedrig dosiertes orales Kontrazeptivum Niedrig
dosierte sequentiell kombinierte (sc)
gestagenbetonte HRTzyklische Gestagengabe (2.
Zyklushälfte)
Niedrig dosierte kontinuierlich kombinierte (cc)
HRT
Neueinschätzung nach 8-12 Wochen Therapie, u.U.
Dosisanpassung
Jährliche Neubewertung von nach lokalen
Richtlinien? Indikation ? Mammographie?
Dosis ? Vaginaler Ultraschall und/oder
Endometriumbiopsie? Therapieregime ?
Knochendichtemessung? Risiko/Nutzenanalyse
Vorzeitige MenopauseFrauen mit vorzeitiger
Menopause sollte routinemäßig eine HRT zumindest
bis zum durchschnittlichen Menopausealter (51
Jahre) angeboten werden.

• zu überlegen ist Umstellung auf ccHRT bei
• postmenopausalen Frauen
• regulären Entzugsblutungen
• Frauen ohne irreguläre Blutungen unter scHRT
• oder
• Frauen ohne Blutung unter scHRT

Einige Frauen können eine erhöhte
mammographische Dichte entwickeln, insbesondere
unter einer höher dosierten kontinuierlich-kombini
erten HRT. Um bei solchen Patientinnen
diagnostische Probleme zu vermeiden, kann ein
Absetzen der HRT für 2-4 Wochen vor der
Mammographie in Erwägung gezogen werden.
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Zusammenfassung HRT

• Die Hormonersatztherapie sollte nur verordnet
  werden, wenn eine klare Indikation besteht
  (primär zur Behandlung klimakterischer
  Beschwerden).
• Es gibt keine wirksamen Alternativen zur
  Behandlung vasomotorischer Symptome.
• Die Hormonsubstitution kann bei Frauen mit
  erhöhtem Frakturrisiko eine Anfangsoption zur
  Senkung des Frakturrisikos darstellen.
• Die langfristige Hormonsubstitution ist mit
  einigen zusätzlichen Risiken verbunden.
• Venöse thromboembolische Erkrankungen
• Schlaganfall
• Brustkrebs (nur bei Normalgewicht)
• Die Indikation zur Fortsetzung der
  Hormonbehandlung sollte jährlich überprüft werden.

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Zu den Risiken einer HRT

• Die Indikation zur Fortsetzung der
  Hormonbehandlung sollte jährlich überprüft werden
• Unter besonderer Beachtung der Risiken einer HRT

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HRT Credo

• HRT bedeutet Substitution des fehlenden
  körpereigenen Hormons in subphysiologischer
  Dosis.
• Die Evolution hat nicht eingeplant, dass die
  Lebenserwartung so ansteigt
• Hätten Männer einen so starken klimakterischen
  Hormonabfall, gäbe es für den Mann schon lange
  eine HRT.
• Männer haben höhere Östrogenspiegel als nicht
  behandelte postmenopausale Frauen.

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HRT Credo

• Östrogene sind nicht mutagen oder cancerogen.
• Östrogene wirken evtl. als Promotor auf
  vorhandene noch okkulte Mammacarcinome.

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Bush et al. 2001 Hormontherapie und
Mammakarzinomrisiko
0,1 1 10
0,1 1 10
0,1 1 10
I I I I I I I I I
I I I I I I I I I
I I I I I I I I I
I I I I I I I I I
I I I I I I I I I
I I I I I I I I I
Inzidenz Estrogene Inzidenz Estrogen/Gestagen
Mortalität
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HRT Credo

• Östrogene erhöhen bei genetisch praedisponierten
  Patientinnen das Thromboembolierisiko.

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WHI-Studie relative Risiken unter CEE oder
CEE/MPA
CEE CEE/MPA
Koronare Herzerkrankungen 0,91 ns 1,24 ns (im 1. Jahr 1,81)
Schlaganfall 1,39 1,31 ischämisch 1,44 hämorrhagisch 0,82 ns
Venöse Thromboembolien 1,33 ns 2,06 Übergewicht 3,80 Adipositas 5,61
Mammakarzinom 0,77 ns 1,24
Kolonkarzinom 1,08 0,61
Oberschenkelhals-Frakturen 0,61 0,66
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Relatives Risiko in der Nurses Health
Study (NHS) und der WHI
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HRT Credo

• HRT stellt die beste und günstigste Therapie der
  Wechseljahresbeschwerden dar.
• Östrogene wirken osteoprotektiv.
• Östrogene reduzieren das Risiko kolorektaler
  Carcinome.

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Mechanisms to resist and repair damage

• Zelluläre
• Endokrinologische
• Lifestyle, Therapeutische (Hormonersatz, HRT,
  Alternatives)

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Alternativen zur HRT

• Kräuterextrakte können klimakterische Beschwerden
  lindern ähnlich wie ein Placebo.
• Phytoestrogene können die Knochenresorption
  verlangsamen eine Senkung des Frakturrisikos
  wurde jedoch nicht gezeigt.
• a-adrenerge Agonisten (z.B. Clonidin) haben eine
  moderate Wirkung auf Hitzewallungen.
• hoch-dosierte Gestagene (5-10 mg NETA, 20-40 mg
  MPA oder Megestrolacetat / Tag) führen zu einer
  wirksamen Reduktion der Hitzewallungen. Die
  Langzeit-Auswirkungen sind bisher nicht
  untersucht.

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Alternativen zur HRT

• Tibolon bessert klimakterische Beschwerden und
  erhält den Knochen.
• Eine Senkung des Frakturrisikos konnte nicht
  gezeigt werden.
• Neuroaktive Medikamente (z.B. Selektive
  Serotonin-Wiederaufnahmehemmer SSRIs) haben eine
  moderate Wirkung auf vasomoto-rische Beschwerden.
  Therapieversuch möglich, wenn eine HRT nicht
  geeignet ist.
• Gabapentin kann Hitzewallungen reduzieren.

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Conclusions

• Übe Nachsicht mit Störfällen

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Zusammenfassung

• Menpause subakuter Verlust der Ovarfunktion
• Endokrinologisch gesehen ein Absturz
• Zahlreiche Kompensations- und Reparaturmöglichkeit
  en

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Zusammenfassung

• Kompensations- und Reparaturmöglichkeiten
• Lifestyle Bewegung, Ernährung
• HRT (beachte die Packungsbeilage)
• Alternativen zur HRT

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Zusammenfassung

• Absturz?
• Individuell gesehen Chance zu Veränderung /
  Persönlichkeitswachstum
• Zwingt zur Auseinandersetzung mit Thema Altern

71

• Der wahre Sinn des Lebens besteht darin, Bäume zu
  pflanzen, unter deren Schatten man vermutlich
  selber nie sitzen wird
• Nelson Henderson

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Übliches zur Menopause
Bruno Müller

• www.DerEndokrinologe.ch
• 3010 Bern

73
The International Menopause Society

• The IMS Updated Recommendationson postmenopausal
  hormone therapy
• February 27, 2007
• Climacteric 20071018194

74
Introducing The International Menopause
SocietyThe society for the study of all
aspectsof the climacteric in men and women

• Established in 1978
• Registered as a non-profit organization in
  Geneva, Switzerland
• Central Office in Lancaster, UK

75
Introducing The International Menopause
SocietyOfficers and Board, 20052008

• Officers
• President Amos Pines, IsraelGeneral Secretary
  David Sturdee, UK
• Treasurer Martin Birkhäuser, Switzerland

Board members

• Santiago Palacios, Spain
• James Pickar, USA
• Regine Sitruk-Ware, USA
• Sven Skouby, Denmark

Mark Brincat, Malta Tobie De Villiers, South
Africa Marco Gambacciani, Italy Kobchitt
Limpaphayom, Thailand Frederick Naftolin, USA
Executive Director Jean Wright, UK
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Introducing The International Menopause
SocietyThe Societys Journal,Climacteric

• Editors-in-Chief David W. Sturdee, UKand
  Alastair H. MacLennan, Australia
• Published in six issues per year plus Supplements
• Indexed in Index Medicus, Medline, Current
  Contents
• Impact factor 2.299
• 11th of 52 journals in Obstetrics Gynecology
  section

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Introduction

• The following Recommendations express the views
  of the IMS on the principles of hormone therapy
  (HT) in the peri- and postmenopause periods
• Throughout the Recommendations, the term HT will
  be used to cover all therapies including
  estrogens, progestogens, combined therapies and
  tibolone
• The 2004 IMS Statement is still valid and serves
  as a basis for the current updated Recommendations

Climacteric 20071018194
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Introduction

• The IMS is aware of possible geographical
  variations related to different priorities of
  medical care, different prevalence of diseases,
  and country-specific attitudes of the public, the
  medical community and the health authorities
  toward menopause management, which may all impact
  on hormone therapy

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Introduction

• The following recommendations, therefore, give a
  global and simple overview that serves as a
  common platform on issues related to the various
  aspects of hormone treatment
• These Recommendations were reviewed and discussed
  by representatives of more than 60 national and
  regional menopause societies from all continents
• These Recommendations can be easily adapted and
  modified according to local needs

Climacteric 20071018194
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Part I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY

• Hormone therapy should be part of an overall
  strategy including lifestyle recommendations
  regarding diet, exercise, smoking and alcohol for
  maintaining the health of postmenopausal women

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Part I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY

• HT must be individualized and tailored according
  to symptoms and the need for prevention, as well
  as personal and family history, results of
  relevant investigations, the womans preferences
  and expectations
• The risks and benefits of HT differ for women
  around the time of menopause compared to those
  for older women
• HT includes a wide range of hormonal products and
  routes of administration, with potentially
  different risks and benefits
• The term class effect, when associated with HT,
  is confusing and inappropriate

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Part I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY

• Women experiencing spontaneous or iatrogenic
  menopause before the age of 45 and particularly
  before 40 are at higher risk for cardiovascular
  disease and osteoporosis
• They will benefit from hormone replacement, which
  should be given at least until the normal age of
  menopause

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Part I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY

• Counseling should convey the benefits and risks
  of HT in simple terms, e.g. absolute numbers
  rather than as percentage changes from baseline
  expressed as a relative risk
• This allows a woman and her physician to make a
  well-informed decision about HT

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Part I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY

• HT should not be recommended without a clear
  indication for its use

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Part I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY

• Women taking HT should have at least an annual
  consultation to include a physical examination,
  update of medical history, relevant laboratory
  and imaging investigations and a discussion on
  lifestyle
• There are no reasons to place mandatory
  limitations on the length of treatment
• Whether or not to continue therapy should be
  decided at the discretion of the well-informed
  hormone user and her health professional,
  dependent upon the specific goals and an
  objective estimation of benefits and risks

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Part I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY

• Dosage should be titrated to the lowest effective
  dose
• Lower doses of HT than have been used routinely
  can maintain quality of life in a large
  proportion of users
• Long-term data on lower doses regarding fracture
  risk and cardiovascular implications are still
  lacking

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part I. Governing principles

• Progestogen should be added to systemic estrogen
  for all women with a uterus to prevent
  endometrial hyperplasia and cancer
• Natural progesterone and some progestogens have
  specific beneficial effects that could justify
  their use besides the expected actions on the
  endometrium

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part I. Governing principles

• Low-dose vaginal estrogens administered for the
  relief of urogenital atrophy do not require
  progestogen co-medication
• Direct delivery of progestogen to the endometrial
  cavity from the vagina or by an intrauterine
  system is logical and may minimize systemic
  effects

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part I. Governing principles

• Androgen replacement should be reserved for women
  with clinical signs and symptoms of androgen
  insufficiency
• In women with bilateral oophorectomy or adrenal
  failure, androgen replacement has significant
  beneficial effects, in particular on
  health-related quality of life and sexual
  function

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part II. Benefits of hormone therapyGeneral

• HT remains the most effective therapy for
  vasomotor and estrogen-deficient urogenital
  symptoms
• Other menopause-related complaints, such as joint
  and muscle pains, mood swings, sleep disturbances
  and sexual dysfunction (including reduced libido)
  may improve during HT

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part II. Benefits of hormone therapyGeneral

• Quality of life and sexuality are key factors to
  be considered in the management of the aging
  individual
• The administration of individualized HT
  (including androgenic preparations when
  appropriate) improves both sexuality and overall
  quality of life

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part II. Benefits of hormone therapyPostmenopaus
al osteoporosis

• HT is effective in preventing the bone loss
  associated with the menopause and decreases the
  incidence of all osteoporosis-related fractures,
  including vertebral and hip, even in patients at
  low risk
• Although the magnitude of decline in bone
  turnover correlates with estrogen dosage, even
  lower than standard-dose preparations maintain a
  positive influence on bone indices in most women

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part II. Benefits of hormone therapy
Postmenopausal osteoporosis

• HT is an appropriate first-line therapy in
  postmenopausal women presenting with an increased
  risk for fracture, particularly under the age of
  60 years and for the prevention of bone loss in
  women with premature menopause
• The protective effect of HT on bone mineral
  density declines after cessation of therapy at an
  unpredictable rate, although some degree of
  fracture protection may remain after cessation of
  HT

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part II. Benefits of hormone therapy
Postmenopausal osteoporosis

• The initiation of standard-dose HT is not
  recommended for the sole purpose of the
  prevention of fractures after the age of 60 years
• The continuation of HT after the age of 60 for
  the sole purpose of the prevention of fractures
  should take into account the possible long-term
  effects of the specific dose and method of
  administration of HT, compared to other proven
  therapies

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part II. Benefits of hormone therapyCardiovascul
ar disease

• Cardiovascular disease is the principal cause of
  morbidity and mortality in postmenopausal women
• Major primary prevention measures (besides
  smoking cessation, and diet control) are weight
  loss, blood pressure reduction, and diabetes and
  lipid control
• There is evidence that HT may be cardioprotective
  if started around the time of menopause and
  continued long-term (often referred to as the
  window of opportunity concept)

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part II. Benefits of hormone therapyCardiovascul
ar disease

• HT markedly reduces the risk of diabetes and,
  through improved insulin resistance, it has
  positive effects on other related risk factors
  for cardiovascular disease such as the lipid
  profile and metabolic syndrome
• In women less than 60 years old, recently
  menopausal, without prevalent cardiovascular
  disease, the initiation of HT does not cause
  early harm, and may reduce cardiovascular
  morbidity and mortality
• Continuation of HT beyond the age of 60 should be
  decided as a part of the overall risk-benefit
  analysis

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part II. Benefits of hormone therapy Other

• HT may reduce the risk of colon cancer
• HT initiated around the time of menopause or by
  younger postmenopausal women is associated with a
  reduced risk of Alzheimers disease
• HT has benefits for connective tissue, skin,
  joints and intervertebral disks

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part III. Potential serious adverse effects of HT

• Studies on the risks of postmenopausal hormone
  use have mainly focused on breast and endometrial
  cancer, venous thromboembolism (pulmonary
  embolism or deep vein thrombosis), stroke and
  coronary events

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part III. Potential serious adverse effects of
HTBreast cancer

• The incidence of breast cancer varies in
  different countries. Therefore, currently
  available data cannot necessarily be generalized

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part III. Potential serious adverse effects of
HTBreast cancer

• The degree of association between breast cancer
  and postmenopausal HT remains controversial.
  Women should be reassured that the possible risk
  of breast cancer associated with HT is small
  (less than 0.1 per annum)

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part III. Potential serious adverse effects of
HTBreast cancer

• For combined HT, observational data from the
  Million Women Study suggested that breast cancer
  risk was increased as early as the first year,
  raising serious reservations on possible
  methodologic flaws
• On the contrary, randomized controlled data from
  the Womens Health Initiative (WHI) Study
  indicate that no increased risk is observed in
  women initiating HT, for up to 7 years. It should
  be noted that the majority of subjects in the WHI
  Study were overweight or obese

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part III. Potential serious adverse effects of
HTBreast cancer

• Data from the WHI and Nurses Health Study
  suggest that long-term estrogen-only
  administration for 7 and 15 years, respectively,
  does not increase the risk of breast cancer in
  American women. Recent European observational
  studies suggest that risk may increase after 5
  years
• There are insufficient data to evaluate the
  possible differences in the incidence of breast
  cancer using different types and routes of
  estrogen, natural progesterone and progestogens,
  and androgen administration

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part III. Potential serious adverse effects of
HTBreast cancer

• Baseline mammographic density correlates with
  breast cancer risk. This does not necessarily
  apply to the increase in mammographic density
  induced by HT
• The combined estrogenprogestogen therapy-related
  increase in mammographic density may impede the
  diagnostic interpretation of mammograms

Climacteric 20071018194
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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part III. Potential serious adverse effects of
HT Endometrial cancer

• Unopposed estrogen administration induces a
  dose-related stimulation of the endometrium
• Women with a uterus should have progestogen
  supplementation
• Continuous combined estrogenprogestogen regimens
  are associated with a lower incidence of
  endometrial hyperplasia and cancer than occurs in
  the normal population
• Direct intrauterine delivery systems may have
  advantages
• Regimens containing low-/ultra-low-dose estrogen
  and progestogen cause less endometrial
  stimulation and less bleeding

Climacteric 20071018194
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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part III. Potential serious adverse effects of
HT Thromboembolism and cardiovascular events

• The HT-related risk for serious venous
  thromboembolic events increases with age
  (although minimal until age 60) and is also
  positively associated with obesity and
  thrombophilia
• By avoiding first-pass hepatic metabolism,
  transdermal estrogen may avert the risk
  associated with oral HT
• The impact on the risk of a thromboembolic event
  may also be affected by progestogen, depending on
  the type

Climacteric 20071018194
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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part III. Potential serious adverse effects of
HT Thromboembolism and cardiovascular events

• Late starters of standard-dose HT may have a
  transient slightly increased risk for coronary
  events
• The risk of stroke is correlated with age. HT may
  increase the risk of stroke after the age of 60
• Safety data from studies of low-dose and
  ultra-low-dose regimens of estrogen and
  progestogen are encouraging

Climacteric 20071018194
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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part IV Alternative treatments

• The efficacy and safety of complementary
  alternative medicines have not been demonstrated
  and further studies are required
• Selective serotonin reuptake inhibitors,
  selective noradrenaline reuptake inhibitors and
  gabapentin are effective in reducing vasomotor
  symptoms in short-term studies. Their long-term
  safety needs further evaluation

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part IV Alternative treatments

• There are no medical or scientific reasons to
  recommend unregistered bioidentical hormones
• The measurement of hormone levels in the saliva
  is not clinically useful
• These customized hormonal preparations have not
  been tested in studies, and their purity and
  risks are unknown

Climacteric 20071018194
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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part V Conclusions

• There is urgent need for further research,
  especially into the relative merits of lower
  doses, regimens and routes of administration

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IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL
HORMONE THERAPY
Part V Conclusions

• The safety of HT largely depends on age
• Women younger than 60 years should not be
  concerned about the safety profile of HT
• New data and re-analyses of older studies by
  womens age show that, for most women, the
  potential benefits of HT given for a clear
  indication are many and the risks are few when
  initiated within a few years of menopause

Climacteric 20071018194
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Adjunctive slides

• The following slides may be useful for
  presentation in regard to the IMS Recommendations
• Some slides demonstrate data on which the
  statements are based. This is not, however, a
  full slide presentation on specific topics.
• The IMS is now in the process of developing an
  Educational Slide Kit on the main issues of adult
  womens health and menopause

112
Dose response to estrogen therapyNumber of
moderatesevere hot flushes
80 70 60 50 40 30 20 10 0
Number



0 1 2 3 4 5 6 7 8 9 10 11 12
Adapted from Notelovitz M, et al. Obstet Gynecol
200095726
113
Ultra-low-dose oral therapyEffect on number of
moderate to severe hot flushes by week
significantly (p 0.001)different from placebo










Adapted from Panay N, et al. Climacteric
20071012031
114
HOPE StudyNumber of hot flushes in 13 cycles
10
CEE/MPA
CEE
Placebo
Placebo
0.625
0.625/2.5
8
0.45
0.45/2.5
0.3
0.45/1.5
0.3/1.5
Mean number
6
4
2
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Cycle
Level I
compared to basal levels basal level mean
incidence of hot flushes 12.3 (11.313.8)
Adapted from Utian W, et al. Fertil Steril
200175106579
115
Women's HOPE StudyChanges in severity of hot
flushes over 12 weeks (n 241)
Placebo
Placebo
0.625/2.5
0.625
0.45/2.5
0.45
0.45/1.5
0.3
0.3/1.5
Hot flush severity 1 mild, 2 moderate, 3
severe. Mean hot flush severity at baseline 2.3
(range 2.22.4).EE Efficacy-evaluable
population included women who recorded taking
study medication and had at least 7
moderate-to-severe flushes/week or at least 50
flushes per week at baseline
Adapted from Utian W, et al. Fertil Steril
200175106579
116
Unopposed ultra-low-dose transdermal estradiol

• 417 postmenopausal women (6080 years)
  mean 67 5 years
• Randomly assigned to placebo or transdermal 14
  µg/day for 2 years
• Baseline serum E2 4.8 pg/ml
• On treatment E2 8.6 pg/ml

Johnson SR, et al. Obstet Gynecol 200510577987
117
Unopposed ultra-low-dose transdermal estradiol
Endometrial effects

• Proliferation 8.5 vs. 1.1 p 0.6
• Bleeding 12.4 vs. 8.6 p 0.3
• Atypical hyperplasia 1
• Adenosarcoma 1

Conclusions This therapy apparently causes
little or no endometrial stimulation
Johnson SR, et al. Obstet Gynecol 200510577987
118
WHI population characteristics
WHI EP arm WHI E arm
Mean Mean
Age (years) 63 63.6lt 60 33.4 30.86069 45.3
45.07079 21.3 24.2 Body mass
index 28.5 30.1lt 25 30.4 212529
35.3 34gt 30 34.2 45 Hypertensive
35.7 48
Rossouw JE, et al. J Am Med Assoc
200228832133 The Womens Health Initiative
Steering Committee. J Am Med Assoc
2004291170112
119
Fracture risk in the WHI study
Hazard ratio (95 CI)
Estrogen progestin Estrogen hormone
therapy hormone therapy
Hip 0.67 (0.470.96) 0.61 (0.410.91) Vertebral
0.65 (0.460.92) 0.62 (0.420.93) Total 0.76
(0.690.83) 0.70 (0.630.79)
significant
Adapted from JAMA 20032901729 and JAMA
20042911701
120
WHI unopposed estrogen
Estrogen (n 5076) Placebo (n 5196) Hazard ratio (95 CI) p
Total joint replacement 119 169 0.73 (0.580.93) 0.01
Hip joint replacement 28 53 0.55 (0.350.88) 0.01
Knee joint replacement 93 121 0.8 (0.611.05) 0.11
Compliance more than 80
Adapted from Cirillo, et al. Arthritis Rheumatism
2006
121
WHI results effect of HTon risk of colorectal
cancer

• KaplanMeier estimate

HR 0.5695 nCI 0.380.8195 aCI 0.330.94
Placebo
E P
Adapted from Chlebowski RT, et al. N Engl J Med
20043509911004
122
Effect of HRT/ERT on CHD in postmenopausal women
Timing of initiation
0.56
lt10
0.92
10?19
CEE
1.04
gt 20
0 0.5 1.0 1.5 2.0 2.5
Hazard ratio (95 CI)
Hazard ratios
Years since menopause
0.89
lt10
1.22
10?19
CEE MPA
1.71
gt 20
0 0.5 1.0 1.5 2.0 2.5
Hazard ratio (95 CI)
Data from WHI
123
Coronary events with ET or placebo by age at
baseline
5059 6069 7079
Coronary event
CHD (MI or coronary death)
p 0.07
CABG or PCI
p 0.09
MI, coronary death, CABG,and PCI
p 0.09
MI, coronary death, CABG, PCI, and confirmed
angina
p 0.11
0 0.5 1 1.5 2
Hazard ratio (95 CI)
Adapted from Hsia J, et al.
Arch Intern Med 200616635765
124
HT and risk of cardiovascular disease by years
since menopause
Years since menopause Hazard ratio CI Absolute excess risk (per 10,000 person-years)
lt 10 0.76 0.501.16 -6
1019 1.10 0.841.45 4
gt 20 1.28 1.031.58 17

• p for trend 0.02

Adapted from Rossouw JE, et al. JAMA
2007297146577
125
WHI CEE/MPA study incidence of diabetes
Placebo
Hazard ratio 0.79 95 CI 0.670.93
Incidence
CEE/MPA
Time (years)
Adapted from Margolis KL, et al. Diabetologia
200447117587
126
Annual risks and benefits after 7 years of
estrogen-only HT
Stroke 12
n 10,739
VTE 7
NS
Increase
Per 10,000 woman-years
5 CVD
7 Breast cancer
Decrease
Hip fractures
6
6
Vertebral fractures
..,
All fractures
57
Adapted from JAMA 2004291170112 MacLennan A,
Sturdee D. Climacteric 2004
127
WHI E-only clinical outcomes when initiated age
5059Annual change in risk (all NS)
VTE 1
Increase
Stroke 0.1
Per 10,000 woman-years
Decrease
1 Breast cancer
3 Total deaths
3 CVD
2 Colorectal cancer
7 Global Index
Adapted from JAMA 2004291170112 MacLennan A,
Sturdee D. Climacteric 2004
128
Age-specific incidence of venous thrombosisWHI
study RCT 16,608 women
Age (years)
5059 6069 7079
Placebo E P Placebo E P Placebo E P
Number of cases 13 32 38 76 25 60 Annualized
rate/ 0.8 1.9 1.9 3.5 2.7 6.2 1000
person-years Hazard ratio 1.0 2.27 2.31 4.28
3.37 7.46 95 CI 1.24.3 1.24.4 2.47.7 1.76.6
4.314.4
Cushman M, et al. JAMA 2004292157380
129
Venous thrombosis andbody mass indexWHI study
RCT 16,608 women age 5079 years
Body mass index
lt 25 2530 gt 30
Placebo E P Placebo E P Placebo E P
Number of cases 13 24 24 59 38 83 Annualized
rate/ 0.9 1.6 1.5 3.5 2.5 5.1 1000
person-years Hazard ratio 1.0 1.8 1.6 3.8
2.8 5.6 95 CI 0.93.5 0.83.2 2.16.9 1.55.4 3
.110.1
Cushman M, et al. JAMA 2004292157380
130
VTE route of administrationand
progestogensESTHER study
Route/progestogen Odds ratio 95 CI
Oral 4.2 1.511.6
Transdermal 0.9 0.42.1
Micronized progesterone 0.7 0.31.9
Pregnanes 0.9 0.42.3
Norpregnanes 3.9 1.510.0
Canonico M, et al. Circulation 20071158202
131
Relation of years since menopause to progression
of atherosclerosis
Adventitia
Media
Internalelasticlamina
Fatty streak/plaque
Years postmenopause of WHI enrollees
132
Postmenopausal hormone use and coronary heart
disease, NHS 19762000 Timing of hormone
initiation with respect to age
Excluding postmenopausal women with prevalent CHD
RR (95 CI)
5059 years
60 years
0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
Adjusted for age, body mass index,
hypercholesterolemia, hypertension, parental
coronary heart disease, diabetes, cigarette
smoking, dietary data, husbands education,
alcohol intake, physical activity, vitamin E or
multivitamin supplementation, aspirin use
Adapted from Grodstein F, et al. J Womens Health
2006153544
133
Coronary heart disease events associated with
hormone therapy in younger and older women a
meta-analysis
23 trials, with 39,049 participants followed for
191,340 patient-years Odds ratio for total
mortality
lt 60 years
0.68 (CI, 0.480.96)
gt 60 years
1.03 (CI, 0.911.16)
0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
Statistical significance
Adapted from Salpeter SR, et al. J Gen Intern Med
2006213636
134
Summary of published results on incidence of
endometrial cancer in relation to use of hormone
therapy (HT)
Type of HT Relative risk (95 CI)
Unopposed estrogen lt 1 year 1.4 (1.01.8)14
years 2.8 (2.33.5)59 years 5.9 (4.77.5)10
years 9.5 (7.412.3) Sequential E P ever vs.
never 1.3 (1.11.4) CCEPT from WHI 0.8 (0.51.4)
CCEPT, continuous combined estrogen and
progestogenE, estrogen P, progestogen
Adapted from Grady D, et al. Obstet Gynecol
19958530413Beral V, et al. J Epidemiol
Biostat 19994191215Anderson GL, et al. JAMA
2003290173944
135
Endometrial hyperplasia rates after 1 and 2 years
of low-dose estrogen progestogen
Womens HOPE Study
Hyperplasia rate ()
0.00
0.00
0.00
0.00
0.00
0.00
0.625 mg
0.625/2.5 mg
0.45 mg
0.45/2.5 mg
0.45/1.5 mg
0.3 mg
0.3/1.5 mg
Placebo
CEE
CEE/MPA
CEE, conjugated equine estrogens MPA,
medroxyprogesterone acetate
Adapted from Pickar JH, et al. Fertil Steril
200380123440
136
Effect of CEE, CEE/MPAon vaginal
maturationWomen's HOPE Study





Superficial cells (median)
CEE, conjugated equine estrogens MPA,
medroxyprogesterone acetate p lt 0.05 vs.
baseline and placebo for all active treatment
groupsp lt 0.05 vs. CEE 0.625 p lt 0.05 vs.
CEE 0.3/MPA 1.5
Adapted from Utian WH, et al. Fertil Steril
200175106579
137
HT use and risk of colorectal cancer
Jacobs et al. 1994 Newcomb and Storer
1995 Folsom et al. 1995 Troisi et al.
1997 Kampman et al. 1997 Grodstein et al.
1998 Paganini-Hill 1999 Hully et al.
2002 Chlebowski et al. 2004 Meta-analysis
Nanda et al. 1999 Meta-analysis Grodstein et
al. 1999
Relative risk (95 CI)
Statistic refers to colon cancer risk only
Multivariate risk analysis Risk assessment
adjusted for age only Meta-analysis includes
two studies of colorectal cancer mortality
Council on Hormone Education
138
Randomized controlled trials breast cancer
results
HERS II WHI
EP EP E Follow-up 6.8 years 6.2 years 7.1
years RR of BC (ITT) 1.27 1.26 0.80 95 CI
0.81.9 1.01.6 0.621.04 RR of BC (adherent)
1.49 0.67 95 CI 1.131.96 0.470.97
Adapted from Hulley, JAMA 1998, Chlebowski, JAMA
2002, JAMA 2003, Stefanick, JAMA 2006
139
Body mass indexthe risk with hormone therapy is
(more) apparent in lean women

• BMI gt 24.4 kg/m2 no additional riskSchairer C,
  et al. JAMA 200028348591
• BMI gt 26 kg/m2 no additional riskRosenberg L,
  et al. Arch Intern Med 20061667605
• Inverse relationship between the risk and BMI
  with estrogen or combined hormone therapyMillion
  Women Study. Reeves GK, et al. Lancet Oncol
  2006791018
• 80 of users have a BMI lt 25E3N-EPIC. Fournier
  A, et al. Int J Cancer 200511444854

140
Hormone therapy in womenwith breast cancer

• Contradictory results between two randomized
  controlled trials
• HABITS 434 patients, stopped after 2.1 years
• HR 3.3 (1.57.4)Lancet 20043634535
• Stockholm 378 patients, stopped after 4.1 years
• HR 0.82 (0.351.9)JNCI 2005975335
• Heterogeneity between the two studies
• Type of treatment
• Proportion of tamoxifen-treated women (52 vs.
  21)
• Node-positive patients

141
Low-dosage micronized17ß-estradiol calcium
prevent bone loss in postmenopausal women
Effect of micronized 17ß-estradiol calcium on
spinal bone mineral density
Estradiol 2.0 mg
3
Estradiol 1.0 mg
2
Estradiol 0.5 mg
Placebo
1
Mean annual change from baseline
0
-1
-2
-3
-4
-5
p lt 0.001 vs. placebo
Adapted from Ettinger B, et al. Am J Obstet
Gynecol 199216647988
142
Osteoporosis and bone strength

• Genetics Architecture
• Diet Turnover rate
• Exercise Damage accumulation
• Hormones Degree of mineralization

Bone density Bone quality Bone strength
Adapted from The NIH Consensus Development Panel
on Osteoporosis. JAMA 200128578595
143
Different effects of estrogen therapy on
connective tissue
Cerebral changes (Alzheimers decreased)
Genital organs (improved)
Estrogen therapy
Decreased skin thickness (reversed)
CVS effects (including carotids)
Bone loss (stopped and reversed)
Cartilage
144
Cartilage, an estrogen-responsive tissue
300
300

200
200

CTX-II (ng/mmol)
CTX-II (ng/mmol)
100
100
0
0
Pre- menopause
Post- menopause
No HRT
HRT
p lt 0.001
Adapted from Mouritzen, et al. Ann Rheum Dis
2003623326
145
Selective serotonin and/or noradrenaline reuptake
inhibitors

• Newer SNRI formulations
• Extended release venlafaxine
• 51 reduction in hot flushes/sweats
• Less nausea
• Desvenlafaxine succinate in development
• Selective NA 5HT reuptake inhibitor
• Good plasma / brain ratios in animal models

Evans ML, et al. Obstet Gynecol 20051051616
Deecher DC, et al. J Pharmacol Exp Ther
200631865765
146
Lower estrogen levels are associated with
increased prevalence of sexual problems
n 93 significance not reported
Adapted from Sarrel PM. J Womens Health Gend
Based Med 20009S2532 Sarrel PM. Obstet Gynecol
199075S2630
147
Postmenopausal hormone therapyand Alzheimer's
disease risk interaction with age
MIRAGE study 426 cases, 545 family
controls Significant interaction between age and
HT use on AD risk (p 0.03). Protective
association was seen only in the youngest age
tertile (5063 years odds ratio 0.35, 95 CI
0.190.66) HT may protect younger women from AD
or reduce the risk of early-onset forms of AD, or
HT used during the early postmenopause may reduce
AD risk
1.00
0.50
Relative risk
0.10
Never
5063 years
6471 years
7299 years
HT use
Adapted from Henderson VW, et al. MIRAGE Study
Group. J Neurol Neurosurg Psychiatry
2005761035
148
Effect of hormone therapyIncidence of
Alzheimers disease The Cache County Memory Study
0.12 0.10 0.08 0.06 0.04 0.02 0
Women HRT non-users HRT use lt 3 years HRT use
310 years HRT use gt 10 years Men
Discrete annual hazard
65 70 75 80 85 90 95 100
Age (years)
Adapted from Zandi PP, et al. JAMA 200228821239
149
Exercise in themenopause

• Any physical activity is better than being
  sedentary
• Regular exercise reduces total and cardiovascular
  mortality
• Better metabolic profile, balance, muscle
  strength, cognition and quality of life are
  observed in physically active persons. Heart
  events, stroke, fractures and breast cancer are
  significantly less frequent
• Benefits far outweigh possible adverse
  consequences the more the better, but too much
  may cause harm

150
Exercise in themenopause optimal exercise
prescription

• At least 30 minutes of moderate intensity
  exercise, at least three times weekly
• Two additional weekly training sessions of
  resistance exercise may provide further benefit
• Injury to the musculo-articulo-skeletal system
  should be avoided

151
AHA 2006 Diet and Lifestyle Recommendations 1

• Balance calorie intake and physical activity to
  achieve or maintain a healthy body weight
• Consume a diet rich in vegetables and fruits
• Choose whole-grain, high-fiber foods
• Consume fish, especially oily fish, at least
  twice a week

Circulation 200611482
152
AHA 2006 Diet and Lifestyle Recommendations 2

• Limit intake of saturated fat to lt 7 of energy,
  trans fat to lt 1 and cholesterol to lt 300 mg/day
  by choosing lean meats and vegetable
  alternatives, selecting fat-free, 1 fat and
  low-fat products
• Choose and prepare foods with little or no salt
• Increase fiber intake (beans, whole grain, other
  fruits and vegetables)
• If you consume alcohol, do so in moderation
• Quit smoking

Circulation 200611482