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(Unübliches zur) Menopause www.DerEndokrinologe.chBern Bruno Müller.

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Präsentation zum Thema: "(Unübliches zur) Menopause www.DerEndokrinologe.chBern Bruno Müller."—  Präsentation transkript:

1 (Unübliches zur) Menopause Bruno Müller

2 Absturz / Pause oder Abflug? Machen Sie sich selber ein Bild …

3

4 Östradiolanstieg positiver Feedback (Hohlwegeffekt) Ausschüttung von LH Proliferative / Sekretorische Phase 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 Karyopyknose-Index = kernlose, pyknotische kernhaltige Zellen

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7 Pause / Abbruch oder Abflug? Endokrinologisch gesehen ist die Frau überaus komplex gesteuert ….Endokrinologisch gesehen ist die Frau überaus komplex gesteuert …. Leider sind StörfälleLeider sind Störfälle Oder gar definitive Funktionsausfälle vorprogrammiert AbsturzOder gar definitive Funktionsausfälle vorprogrammiert Absturz

8 Inhalte – key points Menopause allgemein:Menopause allgemein: - Altern- Altern - Epidemiologie- Epidemiologie - Reparaturmechanismen- Reparaturmechanismen

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

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11 Altern wir, weil die Menge wichtiger Hormone abnimmt? Oder: nimmt die Hormonkonzentration ab, weil wir altern?

12 Nun sag, wie hast dus mit der Religion? Die berühmte Gretchenfrage!

13 Altern, am Bsp. der Oocyten 5 th SS-Monat 7 million Geburt 1-2 Millionen Pubertät 400, Rascher Oocytenverlust

14 Epidemiologie GeburtLebens- Erwartung Dauer der Menopause

15 Home > Die BZgA > Forschung > Fachdatenbanken/Marktanalysen > 15 Demografische Angaben Quelle: Statistisches Bundesamt, Statistisches Jahrbuch 2007

16 Theories of Aging GeneticGenetic – Aging is programmed into the genes – Certain genes are timekeepers for the aging process Wear and Tear Wear and Tear –Cumulative damage to cells from Metabolic processesMetabolic processes Environmental factorsEnvironmental factors – Mechanisms to resist and repair damage are critical

17 Mechanisms to resist and repair damage ZelluläreZelluläre EndokrinologischeEndokrinologische Lifestyle, Therapeutische (Hormonersatz, HRT, Alternatives)Lifestyle, Therapeutische (Hormonersatz, HRT, Alternatives)

18 N N oxygen glucose SOD CatalaseGPX H2O2H2O2H2O2H2O2 H 2 O + O 2 DefenseEnzymes Cellular Damage and Defense O 2 radicals O OH OH - DNA damage Protein damage Lipid damage Antioxidants (GSH, tocopherols, etc.) RepairProcesses Energy(ATP) Mitochondria Nucleus (DNA) Cell Membrane Cytoplasm -proteins

19 Mechanisms to resist and repair damage ZelluläreZelluläre EndokrinologischeEndokrinologische Lifestyle, Therapeutische (Hormonersatz, HRT, Alternatives)Lifestyle, Therapeutische (Hormonersatz, HRT, Alternatives)

20 Menopause Sympome 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)

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

22 Östrogen- Ausfall und/oder –Entzug = Stress Wie reagiert das Hormonsystem?

23 Higher Centers Neural activity (neurotransmitters) Neural activity (neurotransmitters) Hypothalamus Thyroid Adrenal Testis Ovary Gonads Pituitary posterior anterior Trophic Hormones Trophic Hormones LH FSH LH FSH ACTH TSH GH IGF-I Peripheral Hormones Peripheral Hormones Releasing Factors SUMMARY OF HORMONE PHYSIOLOGY Liver Fat Bone Cartilage Muscle - +

24 Higher Centers Neural activity (neurotransmitters) Neural activity (neurotransmitters) Hypothalamus Thyroid Pituitary posterior anterior Trophic Hormones Trophic Hormones LH FSH LH FSH ACTH TSH Releasing Factors SUMMARY OF HORMONE PHYSIOLOGY T4 80% T3 20% aktives Hormon Konversion zu T3 peripher

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26 Control of androgen secretion

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31 - -

32 (physischer) Stress und endokrines System, Zusammenfassung (physischer) Stress führt zu(physischer) Stress führt zu Arousal der CRF-HPA-AchseArousal der CRF-HPA-Achse vermehrter Cortisol-Produktionvermehrter Cortisol-Produktion sekundärem Abfall von Testosteron (und Östradiol, Anstieg von Prolaktin, nicht gezeigt)sekundärem Abfall von Testosteron (und Östradiol, Anstieg von Prolaktin, nicht gezeigt) und Wachstumshormonund Wachstumshormon Verminderter Produktion (d. Konversion) von aktivem Schilddrüsen-Hormon T3Verminderter Produktion (d. Konversion) von aktivem Schilddrüsen-Hormon T3

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

34 Age-related Changes in Body Composition and Function

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

36 Age-related Changes in Body Composition in Normal Sedentary Men Body Composition Age (years) (Balagopal et al. Endocrine 7:57, 1997) Muscle Mass (lbs) Fat (%)

37 Decreases in Muscle Strength with Age (Borges, 1989) (Borges, Scand J Rehabil Med 21:45, 1989) Age (years) Isokinetic Force (Nm) Men Women

38 Altern wir, weil die Menge wichtiger Hormone abnimmt? Oder: nimmt die Hormonkonzentration ab, weil wir altern?

39 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)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 >20% of men by age 65Testosterone (T)- Gradual decline from age 30 onward reaching low (hypogonadal) levels in >20% of men by age 65 Growth Hormone (GH)- Gradual decrease in secretion (and circulating IGF-I levels) from age 45-90Growth Hormone (GH)- Gradual decrease in secretion (and circulating IGF-I levels) from age 45-90

40 How Do Hormones Change with Normal Aging? Adrenal Steroids-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.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 obesityInsulin- loss of sensitivity to insulin action with aging and obesity

41 Mechanisms to resist and repair damage ZelluläreZelluläre EndokrinologischeEndokrinologische Lifestyle, Therapeutische (Hormonersatz, HRT, Alternatives)Lifestyle, Therapeutische (Hormonersatz, HRT, Alternatives)

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

43 Effects of Aging on Growth Hormone Secretion in Men 8:00 am 12:00 pm4:00 pm8:00 pm12:00 am4:00 am8:00 am Time Growth Hormone (ng/ml) Young (Corpas, et al., J Clin Endocrinol Metab 75:530, 1992)

44 Gibt es sonst was zu tun, ausser viel schlafen? Müllersche Frage

45 The International Menopause Society The IMS Updated Recommendations on postmenopausal hormone therapy February 27, 2007 Climacteric 2007;10:181–94

46 Exercise in the menopause 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

47 Exercise in the menopause: 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

48 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 2006;114:82

49 AHA 2006 Diet and Lifestyle Recommendations 2 Limit intake of saturated fat to < 7% of energy, trans fat to < 1% and cholesterol to < 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 2006;114:82

50 Mechanisms to resist and repair damage ZelluläreZelluläre EndokrinologischeEndokrinologische Lifestyle, Therapeutische (Hormonersatz, HRT, Alternatives)Lifestyle, Therapeutische (Hormonersatz, HRT, Alternatives)

51 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

52 Praktische Empfehlungen zur Hormonersatztherapie in der Peri- und Postmenopause Menopausale Einschätzung: Symptome (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 AtrophieMenopausale SymptomeErhöhtes Osteoporoserisiko/Frakturen bei asymptomatischen Frauen Möglich sind: Phytoestrogene α-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 Topisches niedrig dosiertes vaginales Estrogen Niedrig dosierte Estrogenmonotherapie Niedrig dosiertes orales Kontrazeptivum Niedrig dosierte sequentiell kombinierte (sc) gestagenbetonte HRT zyklische Gestagengabe (2. Zyklushälfte) Niedrig dosierte kontinuierlich kombinierte (cc) HRT Neueinschätzung nach 8-12 Wochen Therapie, u.U. Dosisanpassung Jährliche Neubewertung vonnach lokalen Richtlinien: ۰ Indikation ۰ Mammographie** ۰ Dosis ۰ Vaginaler Ultraschall und/oder Endometriumbiopsie ۰ Therapieregime* ۰ Knochendichtemessung ۰ Risiko/Nutzenanalyse Kein Uterus intakter Uterus Peri- meno- pausal Post- meno- pausal Vorzeitige Menopause Frauen 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-kombinierten 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.

53 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.

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

55 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.

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

57 I I I I I I I I I 0, I I I I I I I I I 0, I I I I I I I I I 0, Bush et al Hormontherapie und Mammakarzinomrisiko Inzidenz: Estrogene Inzidenz: Estrogen/Gestagen Mortalität

58 HRT Credo Östrogene erhöhen bei genetisch praedisponierten Patientinnen das Thromboembolierisiko.

59 WHI-Studie relative Risiken unter CEE oder CEE/MPA CEECEE/MPA Koronare Herzerkrankungen0,91 ns1,24 ns (im 1. Jahr 1,81*) Schlaganfall1,39*1,31* ischämisch 1,44* hämorrhagisch 0,82 ns Venöse Thromboembolien1,33 ns2,06* Übergewicht 3,80* Adipositas 5,61* Mammakarzinom0,77 ns1,24* Kolonkarzinom1,080,61* Oberschenkelhals-Frakturen0,61*0,66*

60 Relatives Risiko in der Nurses Health Study (NHS) und der WHI

61

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

63 Mechanisms to resist and repair damage ZelluläreZelluläre EndokrinologischeEndokrinologische Lifestyle, Therapeutische (Hormonersatz, HRT, Alternatives)Lifestyle, Therapeutische (Hormonersatz, HRT, Alternatives)

64 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. -adrenerge Agonisten (z.B. Clonidin) haben eine moderate Wirkung auf Hitzewallungen. hoch-dosierte Gestagene (5-10 mg NETA, mg MPA oder Megestrolacetat / Tag) führen zu einer wirksamen Reduktion der Hitzewallungen. Die Langzeit-Auswirkungen sind bisher nicht untersucht.

65 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.

66 Conclusions Übe Nachsicht mit StörfällenÜbe Nachsicht mit Störfällen

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68 Zusammenfassung Menpause: subakuter Verlust der Ovarfunktion Endokrinologisch gesehen ein Absturz Zahlreiche Kompensations- und Reparaturmöglichkeiten:

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

70 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

72 Übliches zur Menopause Bern Bruno Müller

73 The International Menopause Society The IMS Updated Recommendations on postmenopausal hormone therapy February 27, 2007 Climacteric 2007;10:181–94

74 Introducing The International Menopause Society Introducing The International Menopause Society The society for the study of all aspects of the climacteric in men and women Established in 1978 Registered as a non-profit organization in Geneva, Switzerland Central Office in Lancaster, UK

75 Executive Director: Jean Wright, UK Introducing The International Menopause Society Introducing The International Menopause Society Officers and Board, 2005–2008 Officers President: Amos Pines, Israel General Secretary: David Sturdee, UK Treasurer: Martin Birkhäuser, Switzerland 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 Board members

76 Introducing The International Menopause Society The Societys Journal, Climacteric Editors-in-Chief: David W. Sturdee, UK and Alastair H. MacLennan, Australia Published in six issues per year plus Supplements Indexed in Index Medicus, Medline, Current Contents Impact factor: th of 52 journals in Obstetrics & Gynecology section

77 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 2007;10:181–94

78 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 Climacteric 2007;10:181–94

79 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 2007;10:181–94

80 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 Part I. Governing principles IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

81 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 Part I. Governing principles IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

82 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 Part I. Governing principles IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

83 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 Part I. Governing principles IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

84 HT should not be recommended without a clear indication for its use Part I. Governing principles IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

85 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 Part I. Governing principles IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

86 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 Part I. Governing principles IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

87 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 Part I. Governing principles IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

88 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 Part I. Governing principles IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

89 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 Part I. Governing principles IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

90 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 Part II. Benefits of hormone therapy: General IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

91 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 Part II. Benefits of hormone therapy: General IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

92 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 Part II. Benefits of hormone therapy: Postmenopausal osteoporosis IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

93 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 Part II. Benefits of hormone therapy: Postmenopausal osteoporosis IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

94 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 Part II. Benefits of hormone therapy: Postmenopausal osteoporosis IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

95 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) Part II. Benefits of hormone therapy: Cardiovascular disease IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

96 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 Part II. Benefits of hormone therapy: Cardiovascular disease IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

97 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 Part II. Benefits of hormone therapy: Other IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

98 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 Part III. Potential serious adverse effects of HT IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

99 The incidence of breast cancer varies in different countries. Therefore, currently available data cannot necessarily be generalized Part III. Potential serious adverse effects of HT: Breast cancer IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

100 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) Part III. Potential serious adverse effects of HT: Breast cancer IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

101 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 Part III. Potential serious adverse effects of HT: Breast cancer IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

102 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 Part III. Potential serious adverse effects of HT: Breast cancer IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

103 Baseline mammographic density correlates with breast cancer risk. This does not necessarily apply to the increase in mammographic density induced by HT The combined estrogen–progestogen therapy-related increase in mammographic density may impede the diagnostic interpretation of mammograms Part III. Potential serious adverse effects of HT: Breast cancer IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

104 Unopposed estrogen administration induces a dose-related stimulation of the endometrium Women with a uterus should have progestogen supplementation Continuous combined estrogen–progestogen 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 Part III. Potential serious adverse effects of HT: Endometrial cancer IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

105 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 Part III. Potential serious adverse effects of HT: Thromboembolism and cardiovascular events IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

106 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 Part III. Potential serious adverse effects of HT: Thromboembolism and cardiovascular events IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

107 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 Part IV: Alternative treatments IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

108 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 Part IV: Alternative treatments IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

109 There is urgent need for further research, especially into the relative merits of lower doses, regimens and routes of administration Part V: Conclusions IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY Climacteric 2007;10:181–94

110 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 2007;10:181–94 Part V: Conclusions IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY

111 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 therapy Number of moderate–severe hot flushes Number * ******* ****** Placebo 0.25 mg E2 0.5 mg E2 1 mg E2 2 mg E2 Significantly (p < 0.05) different from placebo * Adapted from Notelovitz M, et al. Obstet Gynecol 2000;95:726

113 * * * significantly (p = 0.001) different from placebo * * * * * * * * Adapted from Panay N, et al. Climacteric 2007;10:120–31 Ultra-low-dose oral therapy Effect on number of moderate to severe hot flushes by week

114 Cycle Mean number * compared to basal levels basal level: mean incidence of hot flushes = 12.3 (11.3–13.8) Placebo 0.625/ / / /1.5 Placebo CEE/MPACEE Level I HOPE Study Number of hot flushes in 13 cycles Adapted from Utian W, et al. Fertil Steril 2001;75:1065–79

115 Hot flush severity: 1 = mild, 2 = moderate, 3 = severe. Mean hot flush severity at baseline = 2.3 (range 2.2–2.4). 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 Placebo / /2.5 Placebo 0.45/ /1.5 Women's HOPE Study Changes in severity of hot flushes over 12 weeks (n = 241) Adapted from Utian W, et al. Fertil Steril 2001;75:1065–79

116 Unopposed ultra-low-dose transdermal estradiol 417 postmenopausal women (60–80 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 2005;105:779–87

117 Unopposed ultra-low-dose transdermal estradiol Proliferation 8.5% vs. 1.1% p = 0.6 Bleeding 12.4% vs. 8.6% p = 0.3 Atypical hyperplasia × 1 Adenosarcoma × 1 Johnson SR, et al. Obstet Gynecol 2005;105:779–87 Conclusions: This therapy apparently causes little or no endometrial stimulation Endometrial effects:

118 Age (years) < – – Body mass index Hypertensive Rossouw JE, et al. J Am Med Assoc 2002;288:321–33 The Womens Health Initiative Steering Committee. J Am Med Assoc 2004;291:1701–12 WHI population characteristics WHI EP armWHI E arm Mean%Mean%

119 * significant Adapted from JAMA 2003;290:1729 and JAMA 2004;291:1701 Fracture risk in the WHI study Hazard ratio (95% CI) Estrogen + progestinEstrogen hormone therapyhormone therapy Hip0.67 (0.47–0.96)*0.61 (0.41–0.91)* Vertebral0.65 (0.46–0.92)*0.62 (0.42–0.93)* Total0.76 (0.69–0.83)*0.70 (0.63–0.79)*

120 WHI: unopposed estrogen Compliance more than 80% Adapted from Cirillo, et al. Arthritis Rheumatism 2006 Estrogen (n = 5076) Placebo (n = 5196) Hazard ratio (95% CI) p Total joint replacement (0.58–0.93) 0.01 Hip joint replacement (0.35–0.88) 0.01 Knee joint replacement (0.61–1.05) 0.11

121 HR = % nCI = 0.38– % aCI = 0.33–0.94 Placebo E + P Adapted from Chlebowski RT, et al. N Engl J Med 2004;350:991–1004 WHI results: effect of HT on risk of colorectal cancer Kaplan–Meier estimate

122 0.89< > < > 20 Effect of HRT/ERT on CHD in postmenopausal women CEE + MPA Years since menopause Hazard ratio (95% CI) Hazard ratio (95% CI) Hazard ratios CEE Data from WHI Timing of initiation

123 Adapted from Hsia J, et al. Arch Intern Med 2006;166:357–65 Coronary events with ET or placebo by age at baseline Coronary event CHD (MI or coronary death) CABG or PCI MI, coronary death, CABG, and PCI MI, coronary death, CABG, PCI, and confirmed angina Hazard ratio (95% CI) 50–59 60–69 70–79 p = 0.07 p = 0.09 p =

124 Years since menopause Hazard ratioCI Absolute excess risk (per 10,000 person-years) < – – –1.454 > – Adapted from Rossouw JE, et al. JAMA 2007;297:1465–77 HT and risk of cardiovascular disease by years since menopause p for trend = 0.02

125 WHI CEE/MPA study: incidence of diabetes Incidence Time (years) CEE/MPA (n) Placebo (n) Adapted from Margolis KL, et al. Diabetologia 2004;47:1175–87 Hazard ratio = % CI = 0.67–0.93 Placebo CEE/MPA

126 Annual risks and benefits after 7 years of estrogen-only HT 5 CVD* VTE* 7 Breast cancer* Hip fractures Per 10,000 woman-years Increase Decrease Stroke 12 Vertebral fractures..,.., All fractures Adapted from JAMA 2004;291:1701–12 MacLennan A, Sturdee D. Climacteric 2004 * = NS n = 10,739

127 WHI E-only clinical outcomes when initiated age 50–59 Annual change in risk (all NS) 3 CVD VTE 1 Breast cancer 2 Colorectal cancer Per 10,000 woman-years Increase Decrease Stroke Global Index 3 Total deaths Adapted from JAMA 2004;291:1701–12 MacLennan A, Sturdee D. Climacteric 2004

128 Age-specific incidence of venous thrombosis WHI study; RCT 16,608 women Age-specific incidence of venous thrombosis WHI study; RCT 16,608 women Cushman M, et al. JAMA 2004;292:1573–80 50–59 60–69 70–79 PlaceboE + P PlaceboE + P PlaceboE + P Number of cases Annualized rate/ person-years Hazard ratio % CI1.2–4.31.2–4.42.4–7.71.7–6.64.3–14.4 Age (years)

129 Venous thrombosis and body mass index WHI study; RCT 16,608 women age 50–79 years Cushman M, et al. JAMA 2004;292:1573–80 30 PlaceboE + P PlaceboE + P PlaceboE + P Number of cases Annualized rate/ person-years Hazard ratio % CI0.9–3.50.8–3.22.1–6.91.5–5.43.1–10.1 Body mass index

130 VTE: route of administration and progestogens ESTHER study Route/progestogenOdds ratio95% CI Oral4.21.5–11.6 Transdermal0.90.4–2.1 Micronized progesterone0.70.3–1.9 Pregnanes0.90.4–2.3 Norpregnanes3.91.5–10.0 Canonico M, et al. Circulation 2007;115:820–2

131 Relation of years since menopause to progression of atherosclerosis Adventitia Media Internal elastic lamina 5 to < 10 19% 10 to < 15 21% 15 43% < 5 17% Fatty streak/plaque Fibrous cap Plaque Fibrous cap Necrotic core Plaque Fibrous cap MMP-9 Necrotic core Years postmenopause % of WHI enrollees

132 Postmenopausal hormone use and coronary heart disease, NHS 1976–2000 Timing of hormone initiation with respect to age RR (95% CI) 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 2006;15:35–44 Excluding postmenopausal women with prevalent CHD years 50–59 years

133 Coronary heart disease events associated with hormone therapy in younger and older women: a meta-analysis Adapted from Salpeter SR, et al. J Gen Intern Med 2006;21:363–6 * Statistical significance < 60 years* > 60 years 23 trials, with 39,049 participants followed for 191,340 patient-years Odds ratio for total mortality 0.68 (CI, 0.48–0.96) 1.03 (CI, 0.91–1.16)

134 Summary of published results on incidence of endometrial cancer in relation to use of hormone therapy (HT) Adapted from Grady D, et al. Obstet Gynecol 1995;85:304–13 Beral V, et al. J Epidemiol Biostat 1999;4:191–215 Anderson GL, et al. JAMA 2003;290:1739–44 CCEPT, continuous combined estrogen and progestogen; E, estrogen; P, progestogen Unopposed estrogen < 1 year1.4 (1.0–1.8) 1–4 years2.8 (2.3–3.5) 5–9 years 5.9 (4.7–7.5) 10+ years9.5 (7.4–12.3) Sequential E + P; ever vs. never1.3 (1.1–1.4) CCEPT from WHI 0.8 (0.5–1.4) Type of HTRelative risk (95% CI)

135 CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate Womens HOPE Study Endometrial hyperplasia rates after 1 and 2 years of low-dose estrogen + progestogen Hyperplasia rate (%) mg0.625/ 2.5 mg 0.45 mg0.45/ 2.5 mg 0.45/ 1.5 mg 0.3 mg0.3/ 1.5 mg Placebo CEECEE/MPA 0.00 Year 1 Year 2 Adapted from Pickar JH, et al. Fertil Steril 2003;80:1234–40

136 Effect of CEE, CEE/MPA on vaginal maturation* Women's HOPE Study CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate *p < 0.05 vs. baseline and placebo for all active treatment groups; p < 0.05 vs. CEE 0.625; p < 0.05 vs. CEE 0.3/MPA 1.5 % Superficial cells (median) Treatment groups mg0.625/ 2.5 mg 0.45 mg0.45/ 2.5 mg 0.45/ 1.5 mg 0.3 mg0.3/ 1.5 mg PlaceboCEECEE/MPA Adapted from Utian WH, et al. Fertil Steril 2001;75:1065–79

137 HT use and risk of colorectal cancer 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 Jacobs et al. 1994* Newcomb and Storer 1995* Folsom et al. 1995* Troisi et al Kampman et al Grodstein et al Paganini-Hill 1999 Hully et al Chlebowski et al Meta-analysis: Nanda et al. 1999* Meta-analysis: Grodstein et al § Council on Hormone Education

138 E+PE+PE Follow-up6.8 years6.2 years7.1 years RR of BC (ITT) % CI 0.8 – – – 1.04 RR of BC (adherent) % CI1.13 – – 0.97 Randomized controlled trials: breast cancer results Adapted from Hulley, JAMA 1998, Chlebowski, JAMA 2002, JAMA 2003, Stefanick, JAMA 2006 HERS IIWHI

139 Body mass index: the risk with hormone therapy is (more) apparent in lean women BMI > 24.4 kg/m 2 – no additional risk Schairer C, et al. JAMA 2000;283:485–91 BMI > 26 kg/m 2 – no additional risk Rosenberg L, et al. Arch Intern Med 2006;166:760–5 Inverse relationship between the risk and BMI with estrogen or combined hormone therapy Million Women Study. Reeves GK, et al. Lancet Oncol 2006;7:910–18 80% of users have a BMI < 25 E3N-EPIC. Fournier A, et al. Int J Cancer 2005;114:448–54

140 Hormone therapy in women with breast cancer Contradictory results between two randomized controlled trials –HABITS: 434 patients, stopped after 2.1 years HR: 3.3 (1.5–7.4) Lancet 2004;363:453–5 –Stockholm: 378 patients, stopped after 4.1 years HR: 0.82 (0.35–1.9) JNCI 2005;97:533–5 –Heterogeneity between the two studies: Type of treatment Proportion of tamoxifen-treated women (52% vs. 21%) Node-positive patients

141 Low-dosage micronized 17β-estradiol + calcium prevent bone loss in postmenopausal women Estradiol 2.0 mg Estradiol 1.0 mg Estradiol 0.5 mg Placebo Adapted from Ettinger B, et al. Am J Obstet Gynecol 1992;166:479– Mean annual % change from baseline from baseline * * * Effect of micronized 17β-estradiol + calcium on spinal bone mineral density *p < vs. placebo

142 Bone density+Bone qualityBone strength Osteoporosis and bone strength GeneticsArchitecture DietTurnover rate ExerciseDamage accumulation HormonesDegree of mineralization Adapted from The NIH Consensus Development Panel on Osteoporosis. JAMA 2001;285:785–95

143 Different effects of estrogen therapy on connective tissue Estrogen therapy Decreased skin thickness (reversed) Cerebral changes (Alzheimers decreased) CVS effects (including carotids) Genital organs (improved) Bone loss (stopped and reversed) Cartilage

144 Cartilage, an estrogen-responsive tissue Pre- menopause Post- menopause *** CTX-II (ng/mmol) No HRTHRT *** CTX-II (ng/mmol) Adapted from Mouritzen, et al. Ann Rheum Dis 2003;62:332–6 *p < 0.001

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 2005;105:161–6 Deecher DC, et al. J Pharmacol Exp Ther 2006;318:657–65

146 Lower estrogen levels are associated with increased prevalence of sexual problems Adapted from Sarrel PM. J Womens Health Gend Based Med 2000;9:S25–32 Sarrel PM. Obstet Gynecol 1990;75:S26–30 Adapted from Sarrel PM. J Womens Health Gend Based Med 2000;9:S25–32 Sarrel PM. Obstet Gynecol 1990;75:S26–30 n = 93; significance not reported

147 Never 50–63 years Relative risk –71 years 72–99 years 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 (50–63 years; odds ratio = 0.35, 95% CI= 0.19–0.66) 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 Adapted from Henderson VW, et al.; MIRAGE Study Group. J Neurol Neurosurg Psychiatry 2005;76:103–5 Postmenopausal hormone therapy and Alzheimer's disease risk: interaction with age HT use

148 Effect of hormone therapy Incidence of Alzheimers disease The Cache County Memory Study Age (years) Discrete annual hazard Women HRT non-users HRT use < 3 years HRT use 3–10 years HRT use > 10 years Men Adapted from Zandi PP, et al. JAMA 2002;288:2123–9

149 Exercise in the menopause 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 the menopause: 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 2006;114:82

152 AHA 2006 Diet and Lifestyle Recommendations 2 Limit intake of saturated fat to < 7% of energy, trans fat to < 1% and cholesterol to < 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 2006;114:82


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