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.

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

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

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

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

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

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

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

EMEA Guidance - Dec 2003

HRT no longer first choice for preventing osteoporosis

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

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

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

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

Climacteric 2004; 7: 333-7

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

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

North American Menopause Society Position Statement

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

International Consensus Group Rome 2003, Lucerne 2004 Climacteric 2004 7: 210-216

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

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 2004 7: 210-216

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)

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)

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

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)

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)

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

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

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Conclusions

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

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

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

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

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

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