{"paper_id":"5263f905-c2d4-40be-a0e8-3eba77aa0616","body_text":"Menopause Hormone Therapy  \nand Cardiovascular Health in  \nWomen through the Menopause\nThis Theramex-sponsored symposium took place on 9th May 2024 as \npart of the International Society of Gynecological Endocrinology (ISGE) \nCongress held in Florence, Italy, between 8th–11th May 2024.\nThis is a promotional article funded and reviewed by Theramex, based on an \nindustry-sponsored symposium at the ISGE 2024 Congress. Prescribing information \nfor Evorel® (oestradiol and hemihydrate norethisterone acetate) can be found here. \nPrescribing information for FemSeven® (oestradiol and levonorgestrel) can be found \nhere. Prescribing information for Bijuva® (oestradiol and progesterone) can be found \nhere. Adverse event reporting can be found at the end of the article.\nChairperson: Rossella Nappi1\nSpeakers: Rossella Nappi,1 Katrin Schaudig,2 Petra Stute3\n1. Research Center for Reproductive Medicine and Gynecologic \nEndocrinology–Menopause Unit, IRCCS San Matteo Foundation, \nUniversity of Pavia, Italy\n2. Center for Gynecologic Endocrinology, Hormone Hamburg, Germany\n3. Gynecologic Endocrinology and Reproductive Medicine,  \nDepartment of Obstetrics and Gynecology, University  \nClinic Inselspital Bern, Switzerland\nDisclosure: Nappi is a lecturer and member of advisory boards and/or consultant \nfor Abbott, Astellas, Bayer Pharma, Besins Healthcare, Exeltis, Fidia, \nGedeon Richter, Merck & Co, Novo Nordisk, Organon & Co, Shionogi \nLimited, Theramex, Viatris, and Vichy Laboratories; and has previously \nworked with Boehringer-Ingelheim, Ely Lilly, Endoceutics, HRA, MSD, \nPalatin, Pfizer Inc., TEVA, Warner Chilcott/Procter & Gamble, and \nZambon. Schaudig has received honoraria for lectures or participation \nin advisory boards, as well as reimbursement for travel expenses and \nresearch funding, from Astellas Pharma GmbH, Bayer-Jenapharm \nGmbH, Dr. KADE/Besins Pharma GmbH, Exeltis GmbH, Gedeon Richter \nPharma GmbH, Hexal, Laborarztpraxis Rhein-Main, Viatris GmbH, Novo \nNordisk, and Theramex. Stute has received honoraria for lectures \nand participation on advisory boards, as well as reimbursement of \ntravel expenses over the last 5 years, from Hexal, Besins Healthcare, \nJenapharm, Labatec, Theramex, Gedeon Richter, Astellas, Effik,  \nPierre Fabre, Vifor, Zeller, and Schaper & Brümmer.\nAcknowledgements: Writing assistance was provided by Rachel Danks,  \nRSD Medical Communications Ltd, Gloucestershire, UK.\nKeywords: Body-identical hormones, cardiovascular health, dydrogesterone, \nhormone replacement therapy (HRT), major cardiovascular events \n(MACE), menopause, menopause management, menopausal hormone \ntherapy (MHT), menopausal transition, micronised progesterone, \noestradiol, perimenopause, post-menopause, progesterone, \nprogestogens, real-world evidence.\nCitation: EMJ Repro Health. 2025;11[Suppl 1]:2-10.  \nhttps://doi.org/10.33590/emjreprohealth/DHPO8497\nSymposium Review\n2 Reproductive Health  ●  March 2025  ●  Copyright © 2025 EMJ   ●   Cover Image © efired / AdobeStock\n\nCC BY-NC 4.0 Licence  ●  Copyright © 2025 EMJ   ●   March 2025  ●  Reproductive Health 3\nIntroduction\nOestrogen deficiency during menopause \nis associated with a number of different \nsymptoms, including vasomotor symptoms \nsuch as hot flashes and night sweats; \npsychological effects, such as sleep \ndisturbances, anxiety, and mood changes; \nphysical discomfort, such as joint and \nmuscle pain; and genitourinary symptoms.1 \nIt has also been shown that women with \nsymptoms of menopause tend to have a \nlower health-related quality of life and an \nincreased need for healthcare services \ncompared with women without symptoms.1\nMenopausal symptoms may be relieved \nby counteracting falling oestrogen levels \nthrough the use of MHT.1 However, despite \nthe evidence supporting the use of MHT, \nuptake of this therapy remains low, with \nmany women expressing ongoing concerns \nabout adopting MHT.1,2 This is largely \na legacy of the 2002 Women’s Health \nInitiative (WHI) study of CEE/MPA in post-\nmenopausal women, which was terminated \nprematurely due to an increased risk of \nbreast cancer with no improvement in \ncardiovascular risk.3 In the years since the \nearly discontinuation of the WHI study, \nprogress has been made in understanding \nthe risk–benefit profile of MHT in terms of \nits timing and duration of use, and also in \nhow body-identical MHT may offer benefits \nover conventional non-body-identical MHT.1 \nSeveral international societies recognise \nMHT as an effective option for alleviating \nmenopausal symptoms by addressing \ndeclining oestrogen levels.1,4-7 Women \nwith an intact uterus are recommended \nto receive MHT in the form of oestrogen \ncombined with a progestogen to protect \nthe uterus from endometrial cancer, while \nwomen who have had a hysterectomy are \nprescribed oestrogen alone.1\nThis symposium explored the importance \nof tailoring MHT to the needs of individual \nwomen, including the impact of type of \nprogesterone on cardiovascular risk.\nMeeting Summary\nThis article summarises a Theramex-sponsored symposium delivered on 9th \nMay 2024 as part of the International Society of Gynecological Endocrinology (ISGE) \nCongress in Florence, Italy, between 8th–11th May 2024. A distinguished panel of \nexperts elaborated on different aspects of cardiovascular health in women receiving \nmenopausal hormone therapy (MHT). Rossella Nappi, Research Center for Reproductive \nMedicine and Gynecologic Endocrinology–Menopause Unit, IRCCS San Matteo \nFoundation, University of Pavia, Italy, chaired and opened the symposium with an \noverview of cardiovascular risk in women, particularly during the menopause transition, \nand described the benefit of oestrogen in mitigating cardiovascular risk. She was \nfollowed by Katrin Schaudig, Center for Gynecologic Endocrinology, Hormone Hamburg, \nGermany, who explained the importance of the choice of progestogen and the route \nof oestrogen administration in combined MHT in terms of risk of cardiovascular and \nother events. The final talk was given by Petra Stute, Gynecologic Endocrinology and \nReproductive Medicine, Department of Obstetrics and Gynecology, University Clinic \nInselspital Bern, Switzerland, who presented recent real-world data from the USA \ndatabase to describe the risk of major cardiovascular events (MACE) in menopausal \nwomen treated with oral oestradiol/micronised progesterone in comparison to \nconjugated equine oestrogen (CEE) plus medroxyprogesterone acetate (MPA).\nSupport: This is a promotional article funded and reviewed by Theramex,  \nbased on an industry-sponsored symposium at the  \nISGE 2024 Congress.\nSymposium review\nPHARMA\nPARTNERSHIP\n\n4 Reproductive Health  ●  March 2025  ●  Copyright © 2025 EMJ   ●   CC BY-NC 4.0 Licence\nMenopause and  \nCardiovascular Disease\nNappi presented 2020 US mortality data \nto show that, although heart disease and \nstroke currently claim more lives each year \nthan cancer and chronic lower respiratory \ndisease combined,8 there was a reduction \nin the percentage of US women identifying \nheart disease/heart attack as the leading \ncause of death between 2009–2019, but  \nan increase in those identifying cancer  \nand breast cancer as leading causes.9\nDeclining oestrogen levels and increased \nabdominal fat in postmenopausal women \nlead to unfavourable metabolic changes, \nresulting in increased cardiovascular \nrisk.10 In particular, there is a significant \nacceleration in cardiovascular risk over the \ncourse of the menopause transition when \nlevels of oestrogen are declining, with the \nrate of events increasing beyond what \nwould be expected for chronological ageing \nalone.11 During this phase of a woman’s life, \ncardiometabolic changes can be separated \ninto those associated with chronological \nageing and those that are due to ovarian \nageing, or a combination of the two.12 \nCertain categories of women, including \nthose with elevated BMI, increased waist \ncircumference, unfavourable metabolic \nprofile, hypertension, and unchanged cycle \nlength over the menopausal transition, have \na higher risk of cardiovascular disease.10 In \naddition, the Framingham study showed \nthat those entering menopause before the \nage of 40 years had a four-times increased \nrisk of cardiovascular disease,13 and a \npooled analysis of 301,438 women showed \nthat women with menopause before the \nage of 40 years had a significantly higher \nrisk of cardiovascular disease compared \nwith those who had menopause at age \n50–51 years (hazard ratio [HR]: 1.55; 95% CI: \n1.38–1.73; p<0·0001).14 Women with obesity \nalso have a 64% increased risk of coronary \nheart disease compared with 46% among \nmen who are obese, and female smokers \nhave a 25% greater risk of cardiovascular \ndisease.15 \nThese findings highlight the importance of \nascertaining a full medical history to assess \noverall lifelong cardiovascular health in \norder to identify women with higher risks \nat menopause.16,17 The Lancet Women and \nCardiovascular Disease Commission issued \nrecommendations to reduce the global \nburden of cardiovascular disease across the \nentire lifespan of women by 2030, focusing \non sex-specific differences in cardiovascular \nrisk factors.18,19\nMenopausal Hormone Therapy \nBenefits and Risks: The Choice  \nof Progestogens Matters\nSchaudig began her presentation by \nnoting that MHT may offer both short-term \nbenefits, including relief of menopause \nsymptoms, as well as possible long-term \nbenefits, including protection against \nosteoporosis-related fractures.4 She \nhighlighted that, for women with an intact \nuterus, MHT needs to be a combination \nof oestrogen and progestogen to protect \nagainst endometrial cancer.3,20,21\nSchaudig noted that the route of \nadministration of oestrogen has an impact \non risk of adverse outcomes with MHT. \nFour separate studies reported a lower \nrisk of venous thromboembolism (VTE) \nwith transdermal oestradiol compared \nwith oral oestradiol,22-25 while a case-\ncontrol study showed an increased risk \nof ischaemic stroke with oral but not with \ntransdermal oestrogens.26 Furthermore, the \n2020 recommendations from the British \nMenopause Society (BMS) and Women’s \nHealth Concern (WHC) on hormone \nreplacement therapy in menopausal women \nexplicitly recommend the use of transdermal \noestradiol to mitigate the risk of VTE and \nstroke in women with related risk factors.27\nAs well as the route of administration \nof oestrogen, the type of progestogen \nalso appears to affect the risk of adverse \noutcomes. A large number of different \ntypes of progestogen are available, each \nwith a distinct biological and clinical profile \ndepending on its tissue concentration \nand receptor-binding affinity.28 The WHI \nevaluated the effects of CEE plus MPA \nversus placebo among 16,608 post-\nSymposium Review\n\nCC BY-NC 4.0 Licence  ●  Copyright © 2025 EMJ   ●   March 2025  ●  Reproductive Health 5\nmenopausal women aged between 50–79 \nyears in the USA.3 The study showed that \nabsolute excess risks per 10,000 women-\nyears attributable to CEE plus MPA were \nseven more coronary heart disease events, \neight more strokes, eight more pulmonary \nembolisms (PE), and eight more invasive \nbreast cancers, with decreases in the \nnumber of events per 10,000 women-\nyears in colorectal cancers (six fewer) and \nhip fractures (five fewer), compared with \nplacebo.3 A subsequent subgroup analysis \nshowed that the risk–benefit profile of CEE \nalone was favourable for all outcomes except \nVTE and stroke, including a decreased \nnumber of breast cancer events.29,30\nAs described earlier, the WHI also \nshowed an increased risk of deep vein \nthrombosis and PE with CEE plus MPA \nversus placebo,3 while the addition of \nmicronised progesterone to transdermal \noestradiol does not appear to increase \nthe risk of VTE.22 The case-control study \ndescribed earlier showed an increased \nrisk of ischaemic stroke with norpregnane \nderivatives in combined MHT, but not \nwith progesterone, pregnane derivatives, \nor nortestosterone derivatives.26 \nFinally, evidence from the French case-\ncontrol study ESTHER (Estrogen and \nThromboembolism Risk) and the French \nE3N cohort study showed that, unlike \nprogesterone and pregnane derivatives, \nuse of norpregnane derivatives in oral MHT \nincreased risk of venous thromboembolism \nin post-menopausal women.31\nType of progestogen also appears to have \nan impact on breast cancer risk. The E3N \nStudy reported an HR for development of \ninvasive breast cancer following at least \n5 years of treatment with oestrogen plus \nsynthetic progestogen of 2.02 (95% CI: \n1.81–2.26) compared with 1.31 (95% CI: 1.15–\n1.48) for micronised progesterone, which \nis chemically and biologically identical to \nendogenous progesterone.32 This suggests \nthat using micronised progesterone with \noestradiol may have a different risk profile \nfor breast cancer compared to synthetic \nprogestogens.32 The difference in breast \ncancer risk between MPA and MP in \ncombination with oestrogen has further \nbeen confirmed in meta-analyses up to 5 \nyears33 and a randomised controlled trial \nwith a median follow-up of 5 years.34 \nAn additional potential benefit of oral \nmicronised progesterone is promoting \nquality sleep in menopausal women. In \nrandomised controlled trials predominantly \nenrolling post-menopausal women, oral \nadministration of micronised progesterone \nhad a measurable benefit on various \nsleep outcomes, possibly as a result of its \ngamma-aminobutyric acid type A (GABA) \nreceptor-modulation activity.35\nBecause the route of oestrogen \nadministration and choice of progestogen \nboth have such a profound impact on patient \noutcomes, it is essential to individualise \ntherapy such that it is tailored to patient risk \nfactors, comorbidities, and family history. \nAs progestogens are essential in MHT for \nmenopausal women with a uterus to prevent \nendometrial hyperplasia and reduce cancer \nrisks, it is important to select a progestogen \nwith a favourable safety profile.22 Micronised \nprogesterone appears to be an optimal \nchoice for women in special situations, \nsuch as in the presence of cardiovascular \ndisease, high-density breast tissue, obesity, \nand risk of VTE.36 Furthermore, the use of a \ntransdermal oestrogen should be considered \nin women with related risk factors, such \nas a history of VTE, uncontrolled diabetes, \nhypertension, or obesity.36\nReal-world Evidence: Incidence \nof Cardiovascular Major Adverse \nEvents of Oestradiol/Micronised \nProgesterone in Comparison with \nConjugated Equine Oestrogen/\nMedroxyprogesterone Acetate\nStute reminded the audience that the WHI \nshowed an increased risk of cardiovascular \ndiseases and VTE with CEE/MPA compared \nwith placebo.3 However, she noted that we \nnow have a much greater understanding \nof the importance of the choice of \nprogestogen on cardiovascular risk, and \nobserved that micronised progesterone \nhas a different safety profile compared \nto synthetic progestins such as MPA.37 \nThe Phase III randomised double-blind \nSymposium review\n\n6 Reproductive Health  ●  March 2025  ●  Copyright © 2025 EMJ   ●   CC BY-NC 4.0 Licence\nplacebo-controlled study investigating a \nsingle oral capsule of oestradiol/micronised \nprogesterone combined MHT (E2/P4) \nshowed no clinically significant changes \nin coagulation or metabolic parameters \nfor E2/P4 compared with placebo over \n12 months of observation.38,39 A 2023 \nstudy of 36,061 women, in which the \nanalyses were weighted by the inverse \nprobability of treatment for control of \npotential confounding factors, showed a \nsignificantly lower incidence of VTE for \noral E2/P4 compared with oral CEE/MPA.40 \nHowever, data comparing E2/P4 with CEE/\nMPA on the risk of MACE incidence are \ncurrently lacking. Therefore, the first head-\nto-head retrospective, longitudinal study \nof MACE incidence in menopausal women \ntreated with E2/P4 versus CEE/MPA was \nundertaken, with the results reported for \nthe first time at the symposium.41\nThe study was a retrospective observational \ninvestigation assessing claims from a US \ndatabase capturing data between April \n2019–June 2021. This large study included \naround 36,000 women treated with \n17β-oestradiol E2/micronised progesterone \nP4 (E2/P4) (combined body-identical MHT) \nor CEE/MPA in a real-world setting, and \nfollowed the same design as the previous \nstudy investigating the rate of VTE with \nE2/P4 compared with CEE/MPA (Figure 1) \n(Stevenson et al., Unpublished data).40,41\nWomen were eligible for the study if they \nwere aged at least 40 years, with at least \none prescription for E2/P4 or CEE/MPA. \nWomen were required to have at least one \nmedical claim and at least one pharmacy \nclaim before the index date, as well as \nno hospitalisation with a MACE diagnosis \n(acute myocardial infarction [ICD-10 \ndiagnosis codes: I21.x, I22.x, or procedure \ncode for revascularisation procedure]; \nischaemic or haemorrhagic stroke [ICD-10 \ndiagnosis codes: I61.x, I62.x, I63.x, I64.x]; or \nheart failure [ICD-10 diagnosis codes: I50.x, \nexcluding I50.x2 and I50.8x]). Women were \nexcluded if they had had a MACE event \nin the baseline period or before the index \ndate, or had switched from E2/P4 to CEE/\nMPA or from CEE/MPA to E2/P4 in the 6 \nmonths following the index date (Stevenson \net al., Unpublished data).\n*Earliest of index treatment from E2/P4 to CEE/MPA, or from CEE/MPA to E2/P4, data cut-off date, or end  \nof clinical activity.†\n†Pharmacy-based activity was defined as no gap ≥12 months between two prescription claims (for hormone  \ntherapy or other drugs); medical-based activity was defined as no gap ≥12 months between two medical claims.\nCEE: conjugated equine oestrogen; E2: oestradiol; MACE: major adverse cardiovascular events;  \nMPA: medroxyprogesterone acetate; P4: micronised progesterone. \nFigure 1: Study design: retrospective observational study of US claims database (major adverse cardiovascular \nevents study) (Stevenson et al., Unpublished data).\nCEE/MPA cohort (n= 29,426  \nE2/P4 cohort (n=6,520  \n6 months continuous clinical activity†\nBASELINE PERIOD\n             First MACE event\nOBSERVATION PERIOD\nData end \nJune 2021\nINDEX DATE \n(first dispensing of  \nE2/P4 or CEE/MPA\nPatient’s first \nclaim in the data\nEnd of \nobservation*\nData start \nApril 2019\n1 pharmacy claim \n1 medical claim \nNo MACE \nPatient characteristics\nSymposium Review\n\nCC BY-NC 4.0 Licence  ●  Copyright © 2025 EMJ   ●   March 2025  ●  Reproductive Health 7\nAn inverse probability of treatment \nweighting (IPTW) analysis of the baseline \ncharacteristics of the MACE study revealed \nthat the mean age of the women was \n54.7–55.8 years, and a high proportion of \nparticipants had cardiovascular disease \n(39.7–41.9%), diabetes (10.7–11.1%), or \nhypercholesterolaemia (28.1–29.4%) at \nbaseline (Stevenson et al., Unpublished \ndata). Approximately 60% of women in \nboth groups were taking treatment for \nsleep disorders, depression, or anxiety, \nand around 40% were taking analgesics \nor relaxants in the post-IPTW analysis \n(Stevenson et al., Unpublished data).\nThe results indicated that women  \ntreated with E2/P4 had a significantly  \nlower risk of MACE events by 72% \ncompared with CEE/MPA (p<0.05; Figure \n2) (Stevenson et al., Unpublished data).  \nAnalysis of the number of MACE events \nper 10,000 women/year showed an early \ndivergence of the two rates curves.\n*Statistically significant at p<0.05.\nCEE: conjugated equine oestrogen; E2: oestradiol; HR: hazard ratio (E2/P4 versus conjugated equine oestrogen/\nmedroxyprogesterone acetate); IPT: inverse probability treatment; IRR: incidence rate ratio (E2/P4 versus CEE/MPA); \nKM: Kaplan-Meier; MPA: medroxyprogesterone acetate; P4: micronised progesterone; WY: women-years.\nFigure 2: Major adverse cardiovascular events rates following inverse probability of treatment for oestrogen/\nmicronised progesterone versus conjugated equine oestrogen/medroxyprogesterone acetate (weighted analysis) \n(Stevenson et al., Unpublished data).\nTime Since Index Date\nPost-IPT Weight\nMACE cumulative incidence HR (95% CI)\nE2/P4 Cohort CEE/MPA Cohort E2/P4 versus CEE/MPA\n3 months 0.08% (0.03–0.23) 0.19% (0.14–0.25)\n0.28 (0.17–0.46)*\n6 months 0.12% (0.05–0.29) 0.37% (0.30–0.44)\n12 months 0.32% (0.18–0.57) 0.78% (0.68–0.90)\n24 months 0.36% (0.20–0.65) 1.79% (1.59–2.02)\nA statistically significant difference was first detected 4 months after treatment initiated  \n(IPT-weighted HR censoring at 4 months: 0.34; 95% CI: 0.14–0.84*)\n2.0%\n1.5%\n1.0%\n% of women \nwith a MACE event0.5%\n0%\nn=5,691 (E2/P4)\nn=29,474 (CEE/MPA)\nIPT-weighted CEE/MPA\nIPT-weighted E2/P4\nn=529 (E2/P4)\nn=4,771 (CEE/MPA)\n0 3 6 9 12 15 18 21 24\nSymposium review\n\n8 Reproductive Health  ●  March 2025  ●  Copyright © 2025 EMJ   ●   CC BY-NC 4.0 Licence\nThe effect was consistent across individual \nMACE outcomes, with significantly more \nevents in the CEE/MPA group than the E2/\nP4 group for heart failure, acute myocardial \ninfarction, and stroke among women aged \nover 40 years (Figure 3) (Stevenson et \nal., Unpublished data). The effect was \nalso consistent across all age subgroups, \nalthough a greater difference in the rate of \nMACE between the two treatment groups \nwas apparent among older women, with \nIPTW analyses stratified by age showing \nhigher MACE event rates in women aged \n60–79 years than those aged 40–59 years \n(MACE events per 10,000 women-years: \n39.5 versus 23.9 for E2/P4 and 145.8 versus \n61.6 for CEE/MPA, respectively) (Stevenson \net al., Unpublished data).\nIn terms of the earlier VTE study, baseline \ncharacteristics revealed that despite the \nrelatively young age of patients in both \ncohorts (mean age: 54.9–55.9 years), there \nwas a high incidence of cardiovascular \ndisease (40.9–42.1%), diabetes (11.2–11.3%), \nhypercholesterolaemia (28.7–29.6%), and \nobesity (9.8–11.0%).40 A post-IPTW analysis \nrevealed that VTE rates were statistically \nlower for E2/P4 compared with CEE/MPA \n(IPTW HR: 0.70; 95% CI: 0.53–0.92).40\nIt should be noted that there are a number \nof limitations associated with the real-\nworld studies, including the fact that \nadministrative claim databases may \ncontain errors or omissions in codes for \ndiagnoses, dispensation, or procedures \n(Stevenson et al., Unpublished data).40,42-44 \nFurthermore, MACE events may have been \nunderestimated because the date of death \nis not captured in the data, while the rate of \nVTE events may be underestimated as only \nthe first VTE event after the index date was \ncounted in the analyses due to difficulties \n*MACE event indexed to person-time post-index date; first MACE event included in the rate numerator;  \nwomen-time up to first event or until end of observation was included in the denominator.\nCEE: conjugated equine oestrogen; E2: oestradiol; IPT: inverse probability treatment; IRR: incidence rate ratio  \n(E2/P4 versus CEE/MPA) (estimated from IPTW Poisson/negative binomial regression models); MACE: major adverse \ncardiovascular events; MPA: medroxyprogesterone acetate; P4: micronised progesterone; WY: women-years.\nFigure 3: Major adverse cardiovascular events rates following inverse probability of treatment for oestrogen/\nmicronised progesterone versus conjugated equine oestrogen/medroxyprogesterone acetate by individual event \n(weighted analysis) (Stevenson et al., Unpublished data).\n9.3\n5.5\n9.6\n29.2\n24.9\n40.5\n9.3\n5.5\n9.6\n29.2\n24.9\n40.5\nSymposium Review\n\nAdverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or \nsearch for MHRA Yellow card in the Google Play or Apple App store. \nAdverse events should also be reported to Theramex on medinfo.uk@theramex.com or Tel: +44 (0)333 0096795\nCC BY-NC 4.0 Licence  ●  Copyright © 2025 EMJ   ●   March 2025  ●  Reproductive Health 9\nin separating new VTE events from \nsubsequent visits for VTE follow-up in the \nclaims data (Stevenson et al., Unpublished \ndata). Finally, residual confounding may \nhave occurred from MACE and VTE \nrisk factors not available in claims data \n(Stevenson et al., Unpublished data).40\nStute concluded that the new real-world \ndata on MACE rates combined with earlier \nVTE data demonstrate a statistically \nsignificant reduction in the rate of MACE \nevents and VTE events associated with \nE2/P4 compared with CEE/MPA in clinical \npractice (Stevenson et al., Unpublished \ndata).40 Although further studies are needed \nto explore this hypothesis, these results \nhighlight the importance of choosing an \noptimum progestogen with a favourable \nsafety profile as part of combined MHT,  \nand in tailoring treatment to ensure the  \nbest outcomes for women.\nReferences\n1. Stute P et al. Reappraising 21 years of \nthe WHI study: putting the findings in \ncontext for clinical practice. Maturitas. \n2023;174:8-13.\n2. Barber K et al. Barriers to accessing \neffective treatment and support for \nmenopausal symptoms: a qualitative \nstudy capturing the behaviours, beliefs \nand experiences of key stakeholders. \nPatient Prefer Adherence. \n2023;17:2971-80.\n3. Rossouw JE et al. Risks and benefits \nof estrogen plus progestin in healthy \npostmenopausal women: principal \nresults from the women's health \ninitiative randomized controlled trial. \nJAMA. 2002;288(3):321-33.\n4. “The 2022 Hormone Therapy Position \nStatement of The North American \nMenopause Society” Advisory Panel. \nThe 2022 hormone therapy position \nstatement of The North American \nMenopause Society. Menopause. \n2022;29(7):767-94.\n5. Sturdee DW et al. Updated IMS \nrecommendations on postmenopausal \nhormone therapy and preventive \nstrategies for midlife health. \nClimacteric. 2011;14(3):302-20.\n6. National Institute for Health and Care \nExcellence. Menopause: diagnosis and \nmanagement. 2019. 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