WEIGHING UP THE RISKS OF HRT. Department of Endocrinology Chris Hani Baragwanath Academic Hospital

Transcription

1 WEIGHING UP THE RISKS OF HRT V. Nicolaou Department of Endocrinology Chris Hani Baragwanath Academic Hospital

2 Background Issues surrounding post menopausal hormonal therapy (PMHT) are complex given: Increased understanding of human biology/physiology Varying terminology used to describe PMHT Differing formulations, doses and modes of therapy Ongoing conflicting data pertaining to the proposed benefits and risks

3 Historical perspective

4 Timeline 1942 Introduction of conjugated equine estrogen (CEE) 1970 Established link between estrogen use and endometrial cancer Sales HRT soared o Sales fell 1980 Introduction of progestins Sales soared 2000 WHI/HERS/PEPI results released

5 Decade of controversy

6 What are we trying to achieve? Hormone replacement Safe Efficacy Accessibile Cost effective

7 CARDIOVASCULAR REPRODUCTIVE SYSTEM SKELETAL OESTROGEN CENTRAL NERVOUS SYSTEM IMMUNE

8 Hormone replacement: what is an oestrogen? Oestradiol/oestrone/oestriol Endogenous OESTROGENS Exogenous SERMS Phytoestrogens Xeno oestrogens

9 Hormone replacement: periodic fluxes in oestrogen Kroenenberg H.M et al, Williams Textbook of Endocrinology Ed 11, 2008

10 Hormone replacement: oestrogen receptor Ligands ER α ER β Genomic Non genomic

11 Hormone replacement: oestrogen metabolism

12 Progestational compounds By definition have progestational activity Divergent range of other properties that can translate to very different clinical effects Absence of a class effect of progestogens.

13 Progestational compounds Types Route Effects Method Progesterone Oral Progestational Sequential Progestins Parenteral Anti oestrogen Continuous Intra uterine Androgenic Anti androgenic Anti minearlocorticoid

14 EFFECTIVENESS OF PMHT? Good evidence that PMHT is effective for the relief of: Vasomotor symptoms Urogenital atrophy BUT What about its role in the in the prevention of or setting of chronic illnesses? Cardiovascular disease Cognition Breast cancer and other oestrogen driven cancers Stroke Mortality

15 Key Landmark trials Landmark trials Understanding the actual risks of PMHT requires interpretation of a complex body of existing data Key RCT which sparked controversy following reassuring data from observational studies pre 1990: PEPI 1997 WHI 1993 HERS I and II 1998/2002 French E3N cohort study Million women study

16 Women's Health Initiative (WHI) What is in a name? Study design: RCT, primary prevention trial Objective: Assess health risks vs. benefits of PMHT Number: Mean age: 63 years Intervention: CEE 0.625mg/d + MPA 2.5mg/day vs placebo Outcome measures: CHD, breast cancer, stroke etc. Results: Manson JE,et al. NEJM 2003

17 CVD HR 1.24 Stroke HR 1.31 VTED HR 2.06 Breast cancer HR 1.26 Manson JE, NEJM 2003

18 HERS I (Heart and Estrogen/Progestin Replacement Study) Study design: RCT, interventional, secondary prevention Objective: to determine whether HRT in women with CHD prevents future disease and events Number: 2763 women with known coronary artery disease and intact uterus Mean age: 66.7yrs Intervention: Continuous CEE 0,625mg plus MPA 2,5mg vs placebo Outcome measures: non fatal MI, CV death Results: More CHD events in the first year with a trend towards reduced risk in years four and five Hulley S. et al, JAMA 1998

19 HERS I: Outcomes Outcome and period Primary CHD events Year 1 Years 4 and 5 Non fatal MI Year 1 Years 4 and 5 CHD death Year 1 Years 4 and 5 Both groups Relative Hazard (95% CI) P value Hulley S, JAMA 1998

20 HERS II unblinded continuation study Objective: To determine if the risk reduction in CHD observed in the later years of HERS I persisted with additional 2.7 years of follow up Outcome: Trend toward reduced risk did not persist In addition no difference in women taking statins or aspirin Grady D et al, JAMA 2002

21 Million women study Study design: Prospective cohort Objective: association between HRT use and reported incidence of breast cancer Number: Mean age: 57 Outcome measures: incidence of breast cancer Results: use of HRT is associated with an increased risk of fatal breast cancer (esp. combined therapy) Beral V. et al, Lancet 2003

22 French E3N cohort study Study design: prospective cohort Objective: assess association between different PMHT regimes and breast cancer risk Number: Mean age: 53.1 years Outcome measures: breast cancer Results: increase breast cancer rates amongst women using combined therapy (particularly androgenic progestins), particularly if used for more than 7 years Fournier A et al. J Clin Oncol 2009

23 Further definite risks of PMHRT Cardiovascular disease Venous thromboembolism Breast cancer Stroke Cholecystitis Santen RJ, JCEM 2010 Sare, G. M M. Eur. Heart J 2008 Bath, P. M. BMJ 2005 Anderson, G. L. Maturitas 2006 Beral, V, J. Natl Cancer Inst (MWS)

24 Definite risks in numbers Definite risks in numbers for 10,000 person years: 7 more CHD events 8 more strokes 8 more pulmonary emboli 8 more invasive breast cancer 14 more cases of cholecystitis

25 Where does this leave the symptomatic post menopausal women and the use of PMHT?

26 Biomedical ethical principles Maleficence Beneficance Justice Autonomy

27 Its not that straight forward...

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