Manuel Neves-e-Castro, MD

Transcription

1 Menopausal Medicine: The past, the present and the future. Where are we now? by Manuel Neves-e-Castro, MD (Lisbon, Portugal) 1 st Postgraduate Academic Course on Menopause EMAS November 2001 Toledo

2 To know how to suggest is the art of teaching (Anonimous)

3 Organotherapy History: The Past Egipt Greece Rome France (1888) Germany (1899)

4 1896: the Begining of HRT Three german groups reported that treatments with ovarian powders relieved symptoms related to the menopause.

5 The devopment of Estrogens(1) Internal secretion :Theophile de Bordeu,1755 Claude Bernard,1885 Hormones :Baylis, Starling William Hardy (UK) Estrogenic effects: - Vagina - Stockard and Papanicolaou Uterus - Allen and Doisy 1924

6 The devopment of estrogens(2) Estrin(Parkes and Bellerby, 1926)Hormone extracted from the ovary with fat solvents. Estrone (Butenandt,1929) isolated in pure form from the urine of pregnant women. Estriol (Marian) isolated from the urine of pregnant women. 17ß-Estradiol (1940) isolated from the urine of pregnant women and from the placenta.

7 The therapeutic use of amniotin in the menopause For hot flashes, sweating, irritability and libido SH Geist and F Spillman Am.J.Obstet.Gynecol.1932;23:

8 The pioneers: the Industry Schering (Germany) Organon (The Netherlands)

9 The first medicines for HRT Progynon Premarin Estradiol Primolut Norlutin ( Schering) (Ayerst) (Implants) (Schering) (Parke Davies)

10 Menopausal Osteoporosis Fuller Albright, 1940

11 Feminine for ever Robert Wilson 1966

12 The Pioneers Robert B.Greenblatt (USA) Wulf H Utian (South Africa and USA) Pieter van Keep (The Netherlands)

13 The Present...

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15 «Health is a condition of physical, mental and social wellbeing and not only the absence of disease.» W.H.O.

16 The assessment of health is far more difficult than the diagnosis of disease. M.N.C. 10/99

17 A menopausal woman is a middle-aged woman

18 As a menopausal woman: She is hypoestrogenic and will suffer, at various levels, from its consequences. MNC 04/00

19 As a middle-aged woman: She will suffer from the process of natural aging, both from a biological and a psychological perspective. MNC 04/00

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22 Menopausal Hormonal Treatments (MHT) The more physiologic (if not contraindicated)

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24 HRT is indicated for: - Relief of symptoms - Maintenance and improvement of health - Prevention (primary and secondary) of diseases

25 Pharmacologic interventions - Symptomatic - Preventive - Primary - Secondary

26 The compression of morbidity J F Fries et al 1981

27 Pharmacologic interventions - hormonal - non hormonal

28 PEPI Trial Not all progestagens are alike

29 The pharmacokinetics and efficacy of different estrogens are not equivalent R.Ansbacher Am.J.Obstet.Gynecol.2001;184:255-63

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33 Breast Cancer

34 1: 397 women taking ERT over 10 yr would develop a breast cancer that would not have ordinarily occurred if ERT were not used. Santen RJ et al. J Clin Endocrinol Metab 2001; 86:16-23

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36 Breast Cancer and HRT CGHFBC-Lancet 1997;350: Cumulative incidence/1000 women (starting at age 50) 5 years 2 new cases 10 years 6 new cases 15 years 12 new cases

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38 HRT and Breast Cancer link still unclear Bush TL et al -Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol 2001;98:

39 The evidence did not support the hypotheses that estrogen use increases the risk of breast cancer and that combined hormone therapy increases the risk more than estrogen only. Aditional observational studies are unlikely to alter this conclusion.

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41 HRT started at age 55 for 10 years can prolong life. One excess breast cancer case is likely to occur per 5-6 averted cases of first myocardial infarction or hip fracture. Moerman CJ, Vanhout BA, BonneuxL, et al. J Intl Med 2000;248(2):

42 Familial Breast Cancer Collaborative reanalysis of individual data from 52 epidemiological studies including women with breast cancer and women without the disease Collaborative Group on Hormonal Factors in Breast Cancer (Oxford) Lancet 2001;358:

43 Familial Breast Cancer 1/9 women who develop breast cancer may have an affected mother, sister or daughter Collaborative Group on Hormonal Factors in Breast Cancer (Oxford) Lancet 2001;358:

44 Familial Breast Cancer Lifetime excess incidence of breast cancer: 5.5% for women with one affected first degree relative 13.3% for women with two affected relatives Collaborative Group on Hormonal Factors in Breast Cancer (Oxford) Lancet 2001;358:

45 Familial Breast Cancer Estimates for death from breast cancer up to age 80: 2.3% for no affected first degree relatives 4.2% for one affected 7.6% for two affected Collaborative Group on Hormonal Factors in Breast Cancer (Oxford) Lancet 2001;358:

46 Physical Exercise Activities and Risk of Breast Cancer 2 to 4 hours / week RR = 0.8 > than 4 hours / week RR = 0.4

47 Relative Risk of Breast Cancer and Body Weight Weight (> 60 kg) and Age (>50 years) increase the RR between 1.2 and 1.8

48 The Heart

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50 HRT prevents a new cardiovascular event in 1: year old women taking HRT for 10 yr. Grodstein F et al. N Engl J Med.2000;335:

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53 The risk for major coronary events was lower among current users of hormone therapy, including shortterm users, compared with never users [(relative risk, 0.61 (95% CI, )]. Grodstein F. et al.ann Intern Med 2000;133:933-41

54 When are observational studies adequate evidence? Grady D. and Hulley SB. Ann Intern Med 2000;133:

55 The HERS trial Does HRT increase CVD events?

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58 he HERS Study, as interpreted by a practitioner, is nothing but a phase III Study of a particular product (0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate, in one tablet daily). Neves-e-Castro M. Maturitas 2001;38(3):

59 It is not a study of estrogen/progestin replacement in postmenopausal women. Neves-e-Castro M. Maturitas 2001;38(3):

60 he protocol of the study does not reflect good clinical practice. Neves-e-Castro M. Maturitas 2001;38(3):

61 The RH comparing risk of the primary CHD outcome in the hormone and placebo group was similar. Hulley S, Grady G, Bush T, et al. JAMA 1998;280:605-13

62 The discrepancy between the finding of HERS and the observational studies may also reflect important differences between the study populations and treatments. Hulley S, Grady G, Bush T, et al. JAMA 1998;280:605-13

63 For women who stopped taking HERS medication, the risk of primary CHD events was elevated in the first month after stopping use of the medication?! Hulley S, Grady G, Bush T, et al. JAMA 1998;280:605-13

64 Hulley S, Grady G, Bush T, et al. JAMA 1998;280: HERS did not evaluate the effect of estrogens plus progestin therapy, in women without CHD, and it is not known whether our findings apply to healthy women. It is also not known whether the use of different progestin or of estrogens alone would have been beneficial.

65 The disappointing results of three recent trials indicate that clinicians should not use hormone therapy for prevention of coronary disease until this practice is supported by evidence from randomised trial! GradyD, Hulley SB.Ann Intern Med 2000;133:

66 Perhaps post-menopausal hormone therapy is beneficial in women who have not yet developed coronary disease but not in women who already have it. Grady D, Hulley SB. Ann Intern Med 2000;133:

67 The findings of HERS should not discourage the use of hormone replacement therapy in the primary prevention of cardiovascular disease. Tolbert T. and Oparil S. Circulation 2001;103:620-2

68 Hormone Replacement Threrapy and Cardiovascular Disease. A Statement for Healthcare Professionals From the American Heart Association. Mosca L et al;circulation.2001;104:

69 Hormone Replacement Therapy and Cardiovascular Disease. There are insufficient data to suggest that HRT should be initiated for the sole (?) purpose of primary prevention on CVD (Circulation 2001)

70 Hormone Replacement Therapy and Cardiovascular Disease. The majority of data available to make clinical recommendations are based on standard doses of oral CEE/MPA. Evidence is insufficient to determine whether different perparations, routes of delivery, doses, or different progestins have a more favorable or more adverse effect on clinical CVD end points (Circulation 2001)

71 Hormone Replacement Therapy and Cardiovascular Disease. In conclusion, recommendations such as these of the AHA (Circulation 2001),writen as they are, may be less helpful than intended, both for clinicians and women. Neves-e-Castro M.The ImaginaryWoman, Maturitas 2001 (in press)

72 HRT and CVD The Effect of Treatment with Estradiol and Norethisterone Acetate on Exercise Tolerance and on the the Frequency and Severity of Ischemic Attacks in Postmenopausal Women with Stable Angina Pectoris. Sanderson JE et al.j Cardiovasc Pharmacol 2001;38(3):

73 HRT and CVD The total number of ischemic events/24 h during ambulatory electrocardiographic monitoring decreased by 0.82 events after treatment compared with an increase in the placebo group (0.94), a highly significant difference (p=0.006). Sanderson JE et al.j Cardiovasc Pharmacol 2001;38(3):

74 The ERA Trial

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76 Epidemiological Studies - How were they performed? - What similarities do they have with our clinical practice? - How to interpret them?

77 Do not confuse Relative Risk with Absolute Risk!

78 Do not confuse Morbility with Mortality!

79 Epidemiological Studies PLEASE! Do not read only the tittles Do not read only the abstracts Do read the full paper Be critical! Make up your own mind! MNC 11/01

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81 The CNS

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86 HRT reduces the incidence of colon cancer

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88 Epidemiology

89 Epidemiological Studies - Observational - Clinical trials

90 What is a woman /year?!

91 100 woman/years = 100 women treated during 12 months is it the same as 100 woman/years = 400 women treated during 3 months?

92 Women are not statistics! They must be treated individually.

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94 Menopausal hormonal treatments are very good. but Treatments without hormones may also be very good for a woman s health

95 When hormone replacement therapy is not possible Neves-e-Castro M in The Management of the Menopause; The Millennium Review 2000 Ed.John Studd; Pathernon, NY 2000

96 HRT is not possible... - When it is not wanted by women. - When women do not feel the need. - When there are contraindications.

97 Look for risk factors - Cardiovascular - Cancer - Bone - CNS

98 New Molecules - Tibolone - Serm s - Bisphosphonates - PTH - ERß ligands - New progestagens - Vitamin D3 derivatives

99 The analysis Benefit/risk Benefit/cost

100 All medical interventions should be individualised to the specific woman s age, characteristics and needs. Genazzani AR, Gambacciani M. IMS Expert Workshop, Climacteric 2000;3:

101 Monitor The efficacy of your interventions in regard to the predetermined objectives/targets

102 For how long?

103 The Future...

104 Life is not to live, but to be well. The first wealth is health. (Anonimous)

105 Hormones?

106 For a woman with high-risk profile, the gains in health are about twice as high as for her counterpart in the general population, and her risk-benefit ratio is also more favourable. Moerman CJ, Vanhout BA, BonneuxL, et al. J Intl Med 2000;248(2):

107 Those who only investigate HRT and never see a patient may have doubts about the enormous benefits of HRT in terms of quality of life.

108 I believe that controlling hormone levels and improving their communication within the body will become the central focus of health care in the future. I also believe they are the key to reversing the aging process. And that is the real goal everyone desires. Barry Sears- The anti-aging Zone. chap.29 Regan Books,NY.1999

109 HRT seems to be the best pharmacological available strategy to improve brain function and to prevent colon cancer

110 Vitamin D derivates convert colon cancer cells Alberto Muñoz et al. Spanish Society for Biochemistry and Molecular Biology (Valencia, September 2001) Lancet Oncology,2:593(October 2001)

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112 Estrogens and Vascular System Estrogens protect the heart against coronary artery disease and they are now regarded as being as important as aspirin and antihypertensive drugs were in the past.

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114 Lipid-lowering therapy promotes clinically stable plaque - Prolonged intensive lipid-lowering therapy is associated with a markedly decreased lipid content in carotid atherosclerotic plaques - The clinical implication of this is that the low plaque lipid composition would predict greater plaque stability, and would thus reduce clinical ischemic events such as myocardial infarction or stroke. Zhao X-Q et al. Arterioscler Thromb Vasc Biol 2001;21: , (October)

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116 Nitroglycerin Therapy Is As Efficacious As Standard Estrogen Replacement Therapy (Premarin) in Prevention of Oophorectomy-Induced Bone Loss: A Human Pilot Clinical Study Wimalawansa, SJ. J Bone Miner Res,2000 Nov, 15(11) p

117 This study showed for the first time that NG is as effective as estrogen in preventing bone loss in these surgically induced menopausal women. Wimalawansa SJ

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119 Although estrogen decreased serum osteocalcin and bonespecific alkaline phosphatase levels, NG therapy significantly increased these two markers of bone formation. Wimalawansa

120 In the future... Will phytoestrogens be usefull for breast protection? MNC 3/01

121 In the future... Will hcg be used, in nuliparous women on HRT, to protect their breast from a cancer risk? (J.Russo) MNC 3/01

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123 In the future Will progesterone medicated IUD s replace oral progestagens in HRT? MNC 3/00

124 HRT To give, or... Not to give?...

125 - The important issue, after all, is not HRT -What is important is the best possible approach to preventive medicine in a middle-aged woman MNC 3/01

126 Can side effects be minimized?

127 First of all, there are many different post-menopausal hormone therapies: different estrogens, different progestins, different routes of administration, different regimens, which have different profiles. Neves-e-Castro M. Maturitas 2001;38(3):

128 Second, there are those who know and those who do not know to tailor-make it to a particular woman and to monitor its efficacy in the targets that have justified its selection. Neves-e-Castro M. Maturitas 2001;38(3):

129 Third, there are those who think that the menopause is a disease to be treated solely with sex hormones, and there are those who believe that the menopause is an event in a middle-aged woman s life. Neves-e-Castro M. Maturitas 2001;38(3):

130 The support of good health and longevity - Aerobic exercise - Rational nutrition - Reduced smoking - Reduced Alchool consumption - Develop Mental ocupations - Pharmacologic interventions

131 Menopausal Treatments for the future? Casper s continuous estrogen/intermittent progestin (Endometrium protection) DHEA-S (Brain, Bone, CNS) Testerone + Estradiol (CNS, Bone) Melatonin (CNS, Cancer) Phytoestrogens (CNS, CV, Cancer) hcg (Breast protection) Estrogens only (Oral or Parenteral) + Progesterone medicated IUD s (Breast and Endomentrium protection) MNC 11/01

132 What do we know today?

133 There are today in the World 470 million women over 50 years of age E.Barrett-Conor, 1993

134 Some concepts to remember...

135 Health Is an essential wealth that must be enriched by all means

136 Health Is a state of physical, psychic and social wellbeing and not only the absence of disease WHO

137 This is the global (holistic) dimension of Health

138 Medicine The Science of - Diagnosing - Treating and - Preventing diseases

139 Preventive Medicine The branch of medical science concerned with the prevention of diseases,with with promotion of physical and mental health through study of aetiology and epidemiology of disease processes Stedman s Medical Dictionary

140 Gynaecology: What is it?

141 Gynaecology = gynaeco + logos i.e. the Science or the Study of the Woman, as a whole.

142 However, today Gynaecology = gynaeco-pathology i.e. the study and treatment of the diseases of women

143 Gynaecology: Is today more concerned with the organic pathology of women, without much consideration of their psychic dimension,and even less with their physical and mental health.

144 The attending physician must - adopt a holistic vision of the middle age woman who comes to him for support. - be concerned and involved in all the aspects that define health. M.N.C. 10/99

145 Attention! -The therapeutic support during the menopause is not confined only to drugs. -It is not the menopause that is going to be treated: -It is a woman,in a very special period of her life,with affective and hormonal imbalances,who needs to be supported and treated as a whole,as she is. M Neves-e-Castro

146 A modern gynecologist must... know how to identify risk factors and to modify them in order to prevent diseases. M.N.C. 10/99

147 As physicians - gynaecologists: Our mission is: 1. To preserve and to promote the physical and mental health of women. 2. To identify and to modify the risk factors that may lead to diseases. 3. To diagnose and to treat their diseases. MNC 10/99

148 Modern gynaecologists : must be: - People - Physicians - and... Specialists MNC 10/99

149 A Menopausal Woman? or A Middle Aged Woman?

150 The Menopause: an opportunity Leon Speroff

151 The Menopause: an alarm clock! M Neves-e-Castro

152 Science... is an art of probability Medicine... is an art of uncertainty Sir William Osler

153 Evidence based Medicine and Medicine based Evidence

154 HRT Hormone replacement therapy? or MHT Menopusal hormonal therapy? MNC 03/00

155 The take home message The prescription of long-term hormonal treatments must depend always on a benefit/risk analysis in comparison with other non-hormonal medications and strategies.

156 Every discussion about the Menopause (the Queen...) seems to implicate that there is nothing but HRT! Neves-e-Castro M. Maturitas 2001;38(3):

157 The Queen... Is naked! Neves-e-Castro M. Maturitas 2001;38(3):

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159 It is very important that the woman understands what is being done and how the objectives are being fulfilled. This is the best way to ensure continuity.

160 The physician must give advice. The woman must take the decision.

161 The physician must give advice. The woman must make the decision.

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163 Preventing a woman from the benefits of a sound postmenopausal hormone therapy because of the fear of rare side effects does not seem to be satisfactory Medicine... MNC 3/01

164 White woman s risk of death between the ages of 50 and 94 are: After Preventing all... For a 10 year a woman long HRT from itthe Only is benefits likely 20% that of women of one may a who avert sound start HRT Good 631.0% postmenopausal cardiovascular seem clinical from to continue heart judgement events disease hormone treatment per after 1 must therapy 2.8% diagnosed 4 years. prevail! from because breast of cancer. the fear of rare side effects does not 2.8% from hip fracture seem to be satisfactory Medicine... Henderson BE et al.arch Intern Med 1991;151:75-8 Pilon D, Castilloux A, Le Lorier J. Obstet Gynecol MNC 2001;97: MNC /01 Brinton LA, Schairer C. N Engl J Med.1997;336:

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166 Menopausal Medicine? Woman s Medicine? Medicine?

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168 Robert B Greenblatt A Woman in the autumn of her life deserves an indian summer rather than a winter of a discontent...

169 WEB SITES (see ligações =links)