1. 2006 : TERAPIA ORMONALE SOSTITUTIVA DELLA MENOPAUSA
CURRENT CONSENSUS GUIDELINES AND PRACTICE RECOMMENDATIONS
Andrea R. Genazzani, MD, PhD, FRCOG
President of the International Society of Gynecological Endocrinology
Director of the Department of Obstetrics and Gynecology
University of Pisa I
Research Support, Grants and Occasional Honoraria: Bracco, Eli Lilly&Company, Igea, Lunar Corporation, MS&D, Novartis, Novo Nordisk, Organon, Pfizer, P&G, Schering, Solvay, Wyeth.

3. An About-Face On Hormone Therapy
New Study Shows HRT May Actually Improve Heart Health in Some Women: Timing Is Key
By Tara Parker-Pope, The Wall Street Journal Jan 24, 2006

4. Guideline and Consensus Recommendations
Practice in areas of controversy can be difficult
HRT has been controversial since 1998
HRT Evidence Base is progressively evolving
Authoritative recommendations provide guidance and a degree of security for practice in these circumstances
Recommendations
Government bodies
International organisations
Consensus Groups

5. Guideline and Consensus Recommendations
Practice in areas of controversy can be difficult
HRT has been controversial since 1998
HRT Evidence Base is progressively evolving
Authoritative recommendations provide guidance and a degree of security for practice in these circumstances
Recommendations
Government bodies
International organisations
Consensus Groups

6. Guideline and Consensus Recommendations
Practice in areas of controversy can be difficult
HRT has been controversial since 1998
HRT Evidence Base is progressively evolving
Authoritative recommendations provide guidance and a degree of security for practice in these circumstances
Recommendations
Government bodies
International organisations
Consensus Groups

7. Guideline and Consensus Recommendations
Government Guidance is minimal EMEA statement
International Societies
International Menopause Society (IMS)
European Menopause and Andropause Society (EMAS)
North American Menopause Society (NAMS)
Consensus Group Recommendations
International Consensus Group
Rome 2003
Lucerne 2004

8. Guideline and Consensus Recommendations
Government Guidance is minimal EMEA statement
International Societies
International Menopause Society (IMS)
European Menopause and Andropause Society (EMAS)
North American Menopause Society (NAMS)
Consensus Group Recommendations
International Consensus Group
Rome 2003
Lucerne 2004

9. Guideline and Consensus Recommendations
Government Guidance is minimal EMEA statement
International Societies
International Menopause Society (IMS)
European Menopause and Andropause Society (EMAS)
North American Menopause Society (NAMS)
Consensus Group Recommendations
International Consensus Group
Rome 2003
Lucerne 2004

10. EMEA Guidance - Dec 2003

11. HRT no longer first choice for preventing osteoporosis

12. these EMEA recommendations are unjustified by:
Physiology
Epidemiology
Pharmachology
Evidence Based Medicine

13. Statement from The International Menopause Society
The International Menopause Society (IMS) is profoundly concerned that the European Medicines Evaluation Agency (EMEA) has ignored important information in its decision to recommend that the risk/benefit balance of hormone replacement therapy (HRT) does not justify its use as first-line therapy for the indication for prevention of osteoporosis in women.
In early postmenopausal women, there is no evidence that alternative treatments are as beneficial……
Because of the age of the population studied in the WHI, safety concerns cannot be extrapolated to early postmenopausal women…………...
Therefore, the IMS considers that the EMEA recommendations are unjustified and potentially harmful for the health of postmenopausal women.

14. EMEA – MHRA Guidance - Dec 2003
HRT provides effective relief of climacteric (vasomotor) symptoms typically occurring around the menopause
The risk:benefit of HRT is favourable for treatment of vasomotor symptoms
The risk:benefit balance of HRT is not favourable as first-line treatment for the prevention of osteoporosis or osteoporotic fractures in women…
with risk factors or
- established osteoporosis

15. EMEA – MHRA Guidance - Dec 2003
HRT provides effective relief of climacteric (vasomotor) symptoms typically occurring around the menopause
The risk:benefit of HRT is favourable for treatment of vasomotor symptoms
The risk:benefit balance of HRT is not favourable as first-line treatment for the prevention of osteoporosis or osteoporotic fractures in women…
with risk factors or
- established osteoporosis

16. Climacteric 2004; 7: 333-7

17. IMS Position Statement
Section 1 Critique of WHI and other recent studies
Section 2 Summary recommendations for practice
Climacteric 2004; 7: 333-7

19. EMAS Position Statement
Section 1 Critique of WHI and other recent studies
Section 2 Recommendations for practice with evidence gradings
Maturitas 2005; 51: 8-14

20. North American Menopause Society Position Statement

21. NAMS Position Statement
Recommendations from Expert Panel Consensus Group – telephone & electronic communication
Discussion of measures of risk and the nature of different types of study
Recommendations for practice
areas of consensus
areas where insufficient or conflicting evidence precludes consensus
the need for future research
Menopause ;

22. International Consensus Group Rome 2003, Lucerne 2004
Climacteric :

23. International Consensus Group Rome 2003, Lucerne 2004
International Expert Group
Extended Consensus Meetings
Burger H (AUS)
Archer DF (USA) Barlow D (UK) Birkhäuser M (CH)
Calaf-Alsina J (E) Gambacciani M (I) Genazzani A (I)
Hadji P (GER) Iversen OE (N) Kuhl H (GER)
Lobo RA (USA) Maudelonde T (F) Neves e Castro M (P)
Notelovitz M (USA) Palacios S (E) Paszkowski T (PL)
Peer E (IL) Pines A (IL) Samsioe G (SWE)
Stevenson J (UK) Skouby S (DK) Sturdee D (UK)
de Villiers T (RSA) Whitehead M (UK) Ylikorkala O (FIN)
Climacteric :

24. International Consensus Group Rome 2003, Lucerne 2004
International Expert Group
Extended Consensus Meetings
Draft Practical Recommendations drafted at meeting by group leaders
Henry Burger & David Archer
Comments received from Group in discussion at meeting and by subsequent electronic communication
Final Recommendations published Climacteric :

25. Indications HRT should only be prescribed when it is clearly indicated
Vasomotor symptoms (there is no effective alternative)
Urogenital atrophy (Topical low-dose products are the treatment choice if only local symptoms present
Fracture risk reduction (HRT may be an initial option in woman at significantly increased fracture risk)

26. Indications HRT should only be prescribed when it is clearly indicated
Vasomotor symptoms (there is no effective alternative)
Urogenital atrophy (Topical low-dose products are the treatment choice if only local symptoms present
Fracture risk reduction (HRT may be an initial option in woman at significantly increased fracture risk)

27. Indications HRT should only be prescribed when it is clearly indicated
Vasomotor symptoms (there is no effective alternative)
Central reason for use of HRT
All guidelines endorse this use (including EMEA advice)
Evidence base secure
No equivalently effective alternative

28. Indications HRT should only be prescribed when it is clearly indicated
Vasomotor symptoms (there is no effective alternative)
Urogenital atrophy (Topical low-dose products are the treatment choice if only local symptoms present
Fracture risk reduction (HRT may be an initial option in woman at significantly increased fracture risk)

29. Indications HRT should only be prescribed when it is clearly indicated
Vasomotor symptoms (there is no effective alternative)
Urogenital atrophy (Topical low-dose products are the treatment choice if only local symptoms present
Important indication for estrogen use
All guidelines endorse this
Local E-only suggested by NAMS & EMAS
Likely to be long term indication (EMAS)

30. Indications HRT should only be prescribed when it is clearly indicated
Vasomotor symptoms (there is no effective alternative)
Urogenital atrophy (Topical low-dose products are the treatment choice if only local symptoms present
Fracture risk reduction (HRT may be an initial option in woman at significantly increased fracture risk)
Evidence agreed by all guidelines
Duration of use needs to be long-term for effective action
no complete consensus from guidelines

31. Indications HRT should only be prescribed when it is clearly indicated
Fracture risk reduction (HRT may be an initial option in woman at significantly increased fracture risk)
Evidence agreed by all guidelines
Duration of use needs to be long-term for effective action
no complete consensus from guidelines
EMEA – not first-line therapy
IMS – Clear endorsement – long term therapy but individualise
EMAS – Best option in younger and symptomatic women
Alternatives more suitable in older women
NAMS – Definite evidence for effect – weigh risks:benefits against alternatives

32. Indications HRT should only be prescribed when it is clearly indicated
Vasomotor symptoms (there is no effective alternative)
Urogenital atrophy (Topical low-dose products are the treatment choice if only local symptoms present
Fracture risk reduction (HRT may be an initial option in woman at significantly increased fracture risk)

33. Initiation of treatment
Early initiation is important – it enables both relief of menopausal symptoms and protects against the consequences of oestrogen deficiency
Combined preparation should be used in women with intact uterus
Sequential (SC) HRT:
 Preferably progestogen-dominant
Bleed free continuous combined (CC) HRT can be recommended later
Switch from SC to CC HRT should meet the following criteria:
 Patient is likely to be postmenopausal (age >50 years)
 Patient should have had regular withdrawal bleeding and no irregular bleeding while taking SC HRT
 Patient had no bleeding on SC HRT

34. Initiation of treatment
Early initiation is important – it enables both relief of menopausal symptoms and protects against the consequences of oestrogen deficiency
Combined preparation should be used in women with intact uterus
All guidelines support early initiation
early relief of symptoms
possible early effects on systemic aspects
NAMS emphasises moderate/severe symptoms as indication

35. Initiation of treatment
Early initiation is important – it enables both relief of menopausal symptoms and protects against the consequences of oestrogen deficiency
Combined preparation should be used in women with intact uterus
Sequential (SC) HRT:
 Preferably progestogen-dominant
Bleed free continuous combined (CC) HRT can be recommended later
Switch from SC to CC HRT should meet the following criteria:
 Patient is likely to be postmenopausal (age >50 years)
 Patient should have had regular withdrawal bleeding and no irregular bleeding while taking SC HRT
 Patient had no bleeding on SC HRT

36. Initiation of treatment
Early initiation is important – it enables both relief of menopausal symptoms and protects against the consequences of oestrogen deficiency
Combined preparation should be used in women with intact uterus
Sequential (SC) HRT:
 Preferably progestogen-dominant
Bleed free continuous combined (CC) HRT can be recommended later
Switch from SC to CC HRT should meet the following criteria:
 Patient is likely to be postmenopausal (age >50 years)
 Patient should have had regular withdrawal bleeding and no irregular bleeding while taking SC HRT
 Patient had no bleeding on SC HRT

37. Initiation of treatment
Early initiation is important – it enables both relief of menopausal symptoms and protects against the consequences of oestrogen deficiency
Combined preparation should be used in women with intact uterus
Sequential (SC) HRT:
 Preferably progestogen-dominant
Bleed free continuous combined (CC) HRT can be recommended later
All guidelines accept that (CC) HRT will be main approach
All recognise that continuous progestogen effect
needs further research

38. Initiation of treatment
Early initiation is important – it enables both relief of menopausal symptoms and protects against the consequences of oestrogen deficiency
Combined preparation should be used in women with intact uterus
Sequential (SC) HRT:
 Preferably progestogen-dominant
Bleed free continuous combined (CC) HRT can be recommended later
Switch from SC to CC HRT should meet the following criteria:
 Patient is likely to be postmenopausal (age >50 years)
 Patient should have had regular withdrawal bleeding and no irregular bleeding while taking SC HRT
 Patient had no bleeding on SC HRT

39. Dose recommendation Lowest effective dose should be used
Recommended starting doses include:
0.5 – 1mg 17β-oestradiol (oral)
0.3 – 0.45mg conjugated equine oestrogens (oral)
25 – 37.5µg transdermal (patch) oestradiol
0.5mg oestradiol gel
150µg intranasal oestradiol

40. Dose recommendation Lowest effective dose should be used
Recommended starting doses include:
0.5 – 1mg 17β-oestradiol (oral)
0.3 – 0.45mg conjugated equine oestrogens (oral)
25 – 37.5µg transdermal (patch) oestradiol
0.5mg oestradiol gel
150µg intranasal oestradiol

41. Monitoring treatment Pre-treatment assessment History
 Menopausal symptoms
 Menstrual history
 Personal and/or family history of
 Osteoporotic fracture
 VTE
 Breast cancer
 CVD
 Physical examination incl. weight and blood pressure
Additional assessments may include/require
Vaginal ultrasound and/or endometrial biopsy
Mammography (frequency according to local guidelines)
Bone mineral density based on local guidelines
Patients should be re-evaluated annually

42. Monitoring treatment Pre-treatment assessment History
 Menopausal symptoms
 Menstrual history
 Personal and/or family history of
 Osteoporotic fracture
 VTE
 Breast cancer
 CVD
 Physical examination incl. weight and blood pressure
Additional assessments may include/require
Vaginal ultrasound and/or endometrial biopsy
Mammography (frequency according to local guidelines)
Bone mineral density based on local guidelines
Patients should be re-evaluated annually

43. Monitoring treatment Pre-treatment assessment History
 Menopausal symptoms
 Menstrual history
 Personal and/or family history of
 Osteoporotic fracture
 VTE
 Breast cancer
 CVD
 Physical examination incl. weight and blood pressure
Additional assessments may include/require
Vaginal ultrasound and/or endometrial biopsy
Mammography (frequency according to local guidelines)
Bone mineral density based on local guidelines
Patients should be re-evaluated annually

44. Duration of treatment Based on the indication for treatment
Dose and type should be re-evaluated annually
Need for continuation can be determined by temporarily discontinuing therapy
Prevention or treatment of osteoporosis
 Only long-term therapy is effective
Urogenital atrophy
 Long-term therapy, usually topical, may be required

45. Duration of treatment Based on the indication for treatment
Dose and type should be re-evaluated annually
Need for continuation can be determined by temporarily discontinuing therapy
Prevention or treatment of osteoporosis
 Only long-term therapy is effective
Urogenital atrophy
 Long-term therapy, usually topical, may be required

46. Duration of treatment Based on the indication for treatment
Dose and type should be re-evaluated annually
Need for continuation can be determined by temporarily discontinuing therapy
Guidelines not entirely consistent
NAMS – extended treatment OK if…
benefit > risk but ? try to stop at intervals
no consensus on stopping – therefore individualise
no consensus on tapering
IMS – No new reason for mandatory limit
No reason to stop when symptom-free on treatment

47. Duration of treatment Based on the indication for treatment
Dose and type should be re-evaluated annually
Need for continuation can be determined by temporarily discontinuing therapy
Prevention or treatment of osteoporosis
 Only long-term therapy is effective
Urogenital atrophy
 Long-term therapy, usually topical, may be required

48. Duration of treatment Based on the indication for treatment
Dose and type should be re-evaluated annually
Need for continuation can be determined by temporarily discontinuing therapy
Prevention or treatment of osteoporosis
 Only long-term therapy is effective
Agreed by all guidelines but differences on effect of this on approach adopted
IMS – strongest view supporting use beyond early PM years

49. Duration of treatment Based on the indication for treatment
Dose and type should be re-evaluated annually
Need for continuation can be determined by temporarily discontinuing therapy
Prevention or treatment of osteoporosis
 Only long-term therapy is effective
Urogenital atrophy
 Long-term therapy, usually topical, may be required

50. Duration of treatment Based on the indication for treatment
Dose and type should be re-evaluated annually
Need for continuation can be determined by temporarily discontinuing therapy
Prevention or treatment of osteoporosis
 Only long-term therapy is effective
Urogenital atrophy
 Long-term therapy, usually topical, may be required
Good consensus across the guidelines in support of
local E-only therapy in extended use

51. Conclusions

52. Conclusions
The international groups demonstrate a good consensus on the use of HRT today
The central role of HRT in symptom relief is unchallenged
The detailed management approach is remarkably similar across the guidelines but all stress the need for individualisation
The longer-term benefits and risks remain controversial and influence longer-term management approaches even where effectiveness is clear – fracture prevention
All criticise a “too simplistic” interpretation of WHI
All agree that more evidence is needed concerning different…...
forms of estrogen and progestogen
routes of administration
levels of hormone dose

53. Conclusions
The international groups demonstrate a good consensus on the use of HRT today
The central role of HRT in symptom relief is unchallenged
The detailed management approach is remarkably similar across the guidelines but all stress the need for individualisation
The longer-term benefits and risks remain controversial and influence longer-term management approaches even where effectiveness is clear – fracture prevention
All criticise a “too simplistic” interpretation of WHI
All agree that more evidence is needed concerning different…...
forms of estrogen and progestogen
routes of administration
levels of hormone dose

54. Conclusions
The international groups demonstrate a good consensus on the use of HRT today
The central role of HRT in symptom relief is unchallenged
The detailed management approach is remarkably similar across the guidelines but all stress the need for individualisation
The longer-term benefits and risks remain controversial and influence longer-term management approaches even where effectiveness is clear – fracture prevention
All criticise a “too simplistic” interpretation of WHI
All agree that more evidence is needed concerning different…...
forms of estrogen and progestogen
routes of administration
levels of hormone dose

55. Conclusions
The international groups demonstrate a good consensus on the use of HRT today
The central role of HRT in symptom relief is unchallenged
The detailed management approach is remarkably similar across the guidelines but all stress the need for individualisation
The longer-term benefits and risks remain controversial and influence longer-term management approaches even where effectiveness is clear – fracture prevention
All criticise a “too simplistic” interpretation of WHI
All agree that more evidence is needed concerning different…...
forms of estrogen and progestogen
routes of administration
levels of hormone dose

56. Conclusions
The international groups demonstrate a good consensus on the use of HRT today
The central role of HRT in symptom relief is unchallenged
The detailed management approach is remarkably similar across the guidelines but all stress the need for individualisation
The longer-term benefits and risks remain controversial and influence longer-term management approaches even where effectiveness is clear – fracture prevention
All criticise a “too simplistic” interpretation of WHI
All agree that more evidence is needed concerning different…...
forms of estrogen and progestogen
routes of administration
levels of hormone dose

57. Conclusions
The international groups demonstrate a good consensus on the use of HRT today
The central role of HRT in symptom relief is unchallenged
The detailed management approach is remarkably similar across the guidelines but all stress the need for individualisation
The longer-term benefits and risks remain controversial and influence longer-term management approaches even where effectiveness is clear – fracture prevention
All criticise a “too simplistic” interpretation of WHI
All agree that more evidence is needed concerning different…...
forms of estrogen and progestogen
routes of administration
levels of hormone dose