Practical Recommendations for Hormone Replacement Therapy

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
Research Support, Grants and Occasional
Honoraria Bracco, Eli LillyCompany, Igea,
Lunar Corporation, MSD, Novartis, Novo Nordisk,
Organon, Pfizer, PG, Schering, Solvay, Wyeth.
2
(No Transcript)
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.

http//www.imsociety.org/pages/news.html
14
EMEA MHRA Guidance - Dec 2003

• HRT provides effective relief of climacteric
  (vasomotor) symptoms typically occurring around
  the menopause
• The riskbenefit of HRT is favourable for
  treatment of vasomotor symptoms
• The riskbenefit 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 riskbenefit of HRT is favourable for
  treatment of vasomotor symptoms
• The riskbenefit 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 1Critique of WHI and other recent
  studies
• Section 2Summary recommendations for practice
• Climacteric 2004 7 333-7

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19
EMAS Position Statement

• Section 1Critique of WHI and other recent
  studies
• Section 2Recommendations for practice with
  evidence gradings
• Maturitas 2005 51 8-14

20
North American Menopause Society Position
Statement

• Menopause 2004. 11 589-600

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 2004. 11 589-600

22
International Consensus Group Rome 2003,
Lucerne 2004

• Climacteric 2004 7 210-216

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 2004 7 210-216

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 publishedClimacteric 2004
  7 210-216

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
  risksbenefits 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
  gt50 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
  gt50 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
  gt50 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
  gt50 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 17ß-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 17ß-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 gt 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