De menopause is een natuurlijk proces. An US Endocrine SocietyScientific Statement July 2010 De menopause is een natuurlijk proces. De behandeling ook. Paul PIETTE Scientific & Medical Affairs Director Mobile + 32 (0) 475 43 69 49 Phone + 32 (0) 333 28 50 – 51 ppiette@besins-healthcare.com LOK, Brugge 17 maart 2011

De goede klinische praktijk beveelt de laagste doeltreffende dosis aan om overgangsklachten te verlichten Belgian Menopause Society. Consensus van de Belgian Menopause Society over hormonale substitutietherapie na de menopauze. Gunaikeia 2009; 14(1): 14-17

Level of Evidence A An Endocrine Society Scientific Statement J Clin Endocrinol Metab 2010; 95 (07): suppl 1. Treatment Initiation with 1,25 g gel to be increased to 2,5 g if necessary Faster efficacy and higher improvement rate of hot flushes severity and frequency with 2,5 g Archer DF (Oestrogel Study Group). Menopause 2003; 10(6): 516-521

Laagste doeltreffende dosis Gemiddeld aantal matige tot ernstige warmteopwellingen gedurende 12 weken behandeling Laagste doeltreffende dosis Notelovitz M, Lenlhan JP, McDermott M, Kerber IJ, Nanavati N, Arce J. Initial 17beta-estradiol dose for treating vasomotor symptoms. Obstet Gynecol 2000 ; 95 : 726-731

Duration of the treatment Arbitrary limitations in duration of usage should be avoided as some women may have symptoms which continue indefinitely and/or may be at significantly increased fracture risk and so warrant long-term usage of HRT. IMS Recommendations 2008 Climacteric 2008; 11(2): 108–123

Level of Evidence A * FDA is updating the public regarding information previously communicated describing the risk of atypical fractures of the thigh, known as subtrochanteric and diaphyseal femur fractures, in patients who take bisphosphonates for osteoporosis. This information will be added to the Warnings and Precautions section of the labels approved to treat osteoporosis, including Fosamax, Fosamax Plus D, Actonel, Actonel with Calcium, Boniva, Atelvia, and Reclast (and their generic products… FDA Announces Change to Bisphosphonate Label On October 2010, 13th the U.S. Food and Drug Administration (FDA) announced a change to the label of bisphosphonates (Fosamax, Actonel, Boniva, and Reclast), a group of drugs used to prevent and treat osteoporosis. The new label will warn about a possible link between the long-term use of these drugs and an increased risk for an atypical femur fracture—a rare type of thigh bone fracture. Although it is not clear from scientific studies whether bisphosphonates are the cause, this type of fracture is reported most often in people taking bisphosphonates. The new label will highlight the possibility that using bisphosphonates for more than five years might raise the risk of this uncommon femur fracture. * New FDA labelling for bisphosphonates “Warnings and Precautions” (October 2010, 13th): Possible link between the long-term use of these drugs (> 5 years ) and an increased risk for an atypical femur fracture, known as subtrochanteric and diaphyseal femur fractures

Level of Evidence A

Level of Evidence A

BMj June 2010 Renoux C et al. BMJ 2010; 340: c2519

Stroke risk by drug type and route of administration Renoux C et al. BMJ 2010; 340: c2519

Stroke risk by dose and by route of administration Renoux C et al. BMJ 2010; 340: c2519

Stroke risk by duration and route of administration Renoux C et al. BMJ 2010; 340: c2519

Stroke risk by HRT type, dose and route of administration in GPRD Renoux C et al. BMJ 2010; 340: c2519

Take Home Message Renoux C et al. BMJ 2010; 340: c2519

Level of Evidence A

HRT and gallbladder disease… New publication in the B.M.J. Liu B et al. Br Med J 2008;337:a386. doi:10.1136/bmj.a386

Key message Use of transdermal oestrogens are associated with a substantially lower risk of gallbladder disease than use of oral oestrogens Over a five year period one cholecystectomy could be avoided for every 140 postmenopausal women of transdermal therapy rather than oral

Selected conclusions with Level of Evidence B

Selected conclusions with Level of Evidence B

Sleep EEG parameters * (min +/- SD) 400 80 P<0.05 200 40 * before treatment (Baseline), at day 21 Placebo or Progesterone (300mg/d) treatment TST = Total Sleep Time SPT = Sleep Period Time Schüssler P et al. Psychoneuroendocrinology 2008; 33: 1124 1131 Caufriez A et al. J Clin Endocrinol Metab 2011. doi:10.1210/jc.2010-2558

Vergelijkende studie betreffende de doeltreffendheid van natuurlijk progesteron op de levenskwaliteit (QoL) Fitzpatrick LA, et al. Comparison of regimens containing oral micronized PG or medroxyPG acetate on quality of life in postmenopausal women: A cross-sectional survey. J Womens Health Gend Based Med. 2000; 9: 381-387

Selected conclusions with Level of Evidence B

Selected conclusions with Level of Evidence C

Review in Maturitas (2008) L’Hermite et al. Maturitas 2008; 60: 185-201.

Relative risks for invasive breast cancer by type of HRT and type of progestagen, compared with HRT never-use (E3N cohort study, N=80.377) 1.60 1.30 1.10 1.00 E2: estradiol; mic P4: micronized progesterone; DHG: dydrogesterone; synt. Prog,: synthetic progestins (mainly nomegestrol acetate, promegestone, chlormadinone acetate, cyproterone acetate, medrogestone) Fournier A et al. Breast Cancer Res Treat 2008; 107: 103-111.

New publication: E3N Study 1990-2002 Relative Risks of Histology-Defined Breast Cancers 1.3 1.7 1.2 1.0 1.1 1.6 2.0 0.5 1.5 2.5 3.0 E2 alone E2 + DHG E2 + synt.P RR Ductal (n= 1,560) Lobulaire (n= 448) E2 + Fournier et al. J Clin Oncol 2008; 26: 1260-1268

Bij het zeer vroegtijdig opstarten van een behandeling vanaf het begin menopauze is de keuze van het progestageen van primordiaal belang La ménopause est naturelle. Son traitement aussi. La ménopause est naturelle. Son traitement aussi.

Follow up van de E3N cohorte van 1992 tot 2005: Hazard Ratios (HR) van invasieve borstkanker* *voor het opstarten van een HST binnen de drie jaar na het begin van de menopauze in functie van: • het type progestageen • de totale behandelingssduur (≤2 jaar of 2-5 jaar) vergeleken met niet-behandelde patiënten (1) Fournier A et al. J Clin Oncol. 2009 ; 27(31): 5138- 5143.

Take Home Message Orale HST op basis van natuurlijk progesteron, opgestart vanaf het begin van de menopauze, wijzigt het risico op borstkanker niet, en dit in tegenstelling tot HST op basis van synthetische progestagenen.

Selected conclusions with Level of Evidence C

New publication in the B.M.J. Canonico et al. BMJ 2008; 336 (7655): 1227-1231

Risk of VTE by characteristics of HRT among users of oral estrogen 2.6 (2.0-3.2) 4.0 (2.9-5.7) 2.1 (1.3-3.8) Canonico et al. BMJ 2008; 336 (7655): 1227-1231

Risk of first episode of VTE by study design and route of oestrogen administration 2.5 (1.9-3.4) 1.2 (0.9-1.7) 2.1 (1.4-3.1) Canonico et al. BMJ 2008; 336 (7655): 1227-1231

The ESTHER Study, VTE risk (oral versus Transdermal) (1.5 – 10.0) 4,5 4 Adjusted Odds Ratio (95% CI) 3,5 3 2,5 2 4,2 (0.4 – 2.1) 1,5 Relative to non-users (never used or past use users of HT), the adjusted odds ratio (OR) for VTE associated with current use of oral and transdermal estrogen therapy were 3.5 (95% CI, 1.8-6.8) and 0.9 (CI, 0.5-1.6), respectively. The adjusted risk for VTE in current users of oral estrogen therapy compared with transdermal estradiol therapy was 4.0 (CI, 1.9-8.3). There was no difference observed in VTE risk between the use of unopposed estrogen and combined estrogen plus progestogen treatment. References: Scarabin PY, Oger E, Plu-Bureau. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362(9382):428-432. 1 0,5 1 0,9 (0.4 – 2.1) nonusers Transdermal Oral Canonico M, Scarabin P. Circulation 2007; 115: 840-845

Conclusions In this large study, we found that route of estrogen administration and concomitant progestogens type are 2 important determinants of thrombotic risk among postmenopausal women using hormone therapy. Transdermal estrogens alone or combined with progesterone might be safe with respect to thrombotic risk. Canonico M et al. Arterioscler Thromb Vasc Biol. 2010; 30(2): 340-345

Hazard Ratios of Idiopathic Venous Thromboembolism in Relation to Both Estrogens by Route of Administration and Concomitant Progestogens Canonico M et al. Arterioscler Thromb Vasc Biol. 2010; 30(2): 340-345

IMS Recommendations The risk of thromboembolic disease is not significantly increased in observational studies of women using transdermal estrogen therapy. Key practice point: Women seeking HRT who have potential or confirmed risk factors for VTE and stroke need individualized counseling; in these situations, transdermal HRT might be preferable to oral formulations.

New publication from GPRD database (May 2010)

Estrogens by route of administration and VTE risk (GPRD study) 1.11 (1.04-1.19) 1.49 (1.37-1.63) 1.54 (1.44-1.65) 1.01 (0.89-1.16) 0.96 (0.77-1.20) Cases/control Adjusted rate ratio* (95% CI) Past use 1107 / 9520 Oral route of administration Estrogen 273 / 2721 Estrogen-progestogen 92 / 1043 No use 19849 / 201985 Transdermal route of administration Estrogen 729 / 5105 Estrogen-progestogen 1277 / 9342 * The rate ratio was adjusted for all characteristics listed in the publication Renoux C et al. J Thromb Haemost 2010; 8: 979-986

Duration of HRT, dose of oral estrogens, and VTE risk (GPRD study) * The rate ratio was adjusted for all characteristics listed in the publication 1.19 (1.04-1.35) 1.55 (1.45-1.65) 1.84 (1.63-2.09) Cases/control Adjusted rate ratio* (95% CI) Oral E low dose 280 / 2468 < 0.625 MG CEE or E2 < 2 MG Oral E very high dose 342 / 1970 Higher daily dose No use 19849 / 201985 Oral E high dose 1384 / 10009 = 0.625 MG CEE or E2 = 2 MG Current exclusive oral estrogen users ≤ 1 year 96 / 447 Current exclusive oral estrogen-progestogen users ≤ 1 year 199 / 1156 2.32 (1.83-2.94) 1.92 (1.63-2.25) Renoux C et al. J Thromb Haemost 2010; 8: 979-986

Take Home Message HST voorgeschreven tijdens de Window of opportunity, bij gezonde gemenopauseerde vrouwen, vermindert op significante wijze het risico op coronair hartlijden. Grodstein F. et al. J Women’s Health. 2006;15(1): 35-44.

EMAS POSITION STATEMENT Summary recommendations Cardiovascular disease is the main cause of death in women. Postmenopausal status is associated with a higher prevalence of coronary heart disease. Randomized controlled trial data show that HT does not have a role in the primary prevention of CHD in women over 50, but most information is limited to conjugated equine estrogens and medroxyprogesterone acetate. HT does not have a role in the secondary prevention of CHD; but the number of patients involved i randomized controlled trials is small. The lowest effective estrogen dose should be used for menopausal symptoms (17beta-estradiol 0.5–1mg orally daily, conjugated equine estrogen 0.3–0.625mg daily orally, or 25–50g 17ß-estradiol transdermally). Schenck-Gustafsson et al. Maturitas 2011; 68: 94-97

EMAS POSITION STATEMENT Summary recommendations Transdermal HT should be the first choice in women either at increased risk of CHD or with pre-existing disease because of its lesser effects on coagulation. Regular follow up by a specialist service is recommended. Observational studies suggest that micronized progesterone or dydrogesterone may have a better risk profile than other progestogens with regard to thrombotic risk. Schenck-Gustafsson et al. Maturitas 2011; 68: 94-97

...de laagste doeltreffende dosis Besluit… ...de laagste doeltreffende dosis ... orale HST op basis van natuurlijk progesteron, opgestart vanaf het begin van de menopauze, wijzigt het risico op borstkanker niet

Take Home message Rehabilitation of the HRT Clinical efficacy, QoL* and sleep improvement The window of opportunity Osteoporosis prevention Cardiovascular protection The same dose does not fit for all women * QoL Quality of Life Climacteric 2008; 11(2): 108–123