How low can you go?

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  • Editorial

    How low can you go?David W. Sturdee and Alastair H. MacLennan

    EDITORS-IN-CHIEF

    Regulatory authorities in North America andEurope have consistently been advocating theuse of the lowest dose of hormone therapy (HT)and for the shortest duration, but what is thelowest dose? The dose of HT that is suitable foreach individual woman will depend particularlyon her age, the indications for treatment and theindividual response. It is well recognized that thedose required for menopausal symptom relief willbe higher in younger women and, in particular,those who have experienced premature ovarianfailure, whether this occurs naturally or is due tosurgery or chemotherapy. The doses required forthis group of women will be in the upper range orabove of regimens currently available. Conversely,older postmenopausal women require much lowerdoses for the same effect.

    It is a principle of good prescribing practice togive the lowest dose of any medication that will beeffective on the assumption that side-effects aredose-related. The risks and side-effects of HT thatwere documented in the Heart and Estrogen/progestin Replacement Study (HERS) andWomens Health Initiative (WHI) studies wereassociated with conjugated equine estrogens (CEE)0.625 mg and medroxyprogesterone acetate(MPA) 2.5 mg daily, given to women in theirmid-sixties, which many commentators have criti-cized as being too high a dose for asymptomaticwomen of this age. Since publication of thesestudies and the regulatory bodies response,increasing numbers of reports and reviews on theeffects of lower doses have appeared13.

    A clinical definition of the lowest dose would bethat which will treat symptoms effectively, whilstmaintaining endometrial safety. However, thelimited range of doses available to us withcurrently licensed pharmaceutical products has

    meant that experimenting with reduced doses hasrequired cutting tablets or patches in half, orincreasing the time between dosages, but these areundesirable, unreliable and unlicensed practices.Several reports have now shown that doses as low asCEE 0.3 mg daily and estradiol 0.5 mg daily canreducehotflushes satisfactorilyand that this effect isenhanced by the addition of progestogen. For boneprotection, however, even lower dosages of estro-gen seem tobeeffective inpreventingbone loss, suchas oral estradiol 0.25 mg daily and just 14mgestradiol daily by patch4. If these doses receiveapproval from the regulatory authorities, theyshould become available for easier prescribing.

    As in all trials that study only one fixedpragmatic regimen and dose, the overall groupeffect masks differing individual responses. Inclinical practice, better effect, less side-effects andgreater continuance with therapy can be achievedwith tailoring of the dose, regimen and route ofadministration to the individual. Thus, a low-doseregimen may be an appropriate starting point formany women, but the clinical response needs to bereviewed after about 3 months to allow indivi-dualized adjustment of the therapy. Persistentprescription of the lowest available dose wherethere is little beneficial effect is a recipe for non-adherence to therapy and a loss of oppurtunity tosee if a more effective dose or route of HT wouldhave brought relief of symptoms. Commencementof a medium dose in a recently menopausalwoman, with a gradual lowering of the dose tofind the lowest effective dose, is another reason-able option and often can be achieved with theaging of the woman should HT still be required toalleviate persistent symptoms.

    This Editorial was written prior to the 11thWorld Congress in Buenos Aires, where it is likely

    CLIMACTERIC 2005;8:305306

    2005 International Menopause SocietyDOI: 10.1080/13697130500401878

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  • there will be papers showing the effect of loweringthe dose of both estrogen and progestogen, at leastin the short term. Data from one multicenter studyof estradiol 0.5 mg with norethisterone acetate0.1 mg or 0.25 mg daily over 6 months are to bepresented and, in addition to providing goodsymptom relief and minimal bleeding, there wasalso no change in mammographic breast density.These findings are encouraging, but unfortunatelyit is unlikely that large, long-term studies,

    equivalent to the WHI and using these doses, willbe performed, so that the potential benefits in areduced risk to the breast and other systems canonly be speculated. A further difficulty is how tocompare the doses of different estrogen prepara-tions and routes of administration. The 0.3 mgCEE and 0.5 mg estradiol preparations are beingtermed ultra low-dose, which implies that therewill not be any even lower doses to come, so wehave probably now reached as low as we can go!

    References

    1. Lobo RA, Whitehead MI. Is low-dose hormone re-placement therapy for postmenopausal women effi-cacious and desirable? Climacteric 2001;4:11019

    2. Archer DF. Lower doses of oral estrogen andprogestogens as treatment for postmenopausalwomen. Semin Reprod Med 2005;23:18895

    3. Peeyananjarassri K, Baber R. Effects of low-dosehormone therapy on menopausal symptoms, bone

    mineral density, endometrium and the cardiovas-cular system: a review of randomized clinicaltrials. Climacteric 2005;8:1323

    4. Ettinger B, Ensrud KE, Wallace R, et al.Effects of ultra low-dose transdermal estra-diol on bone mineral density: a randomisedclinical trial. Obstet Gynecol 2004;104:44351

    Editorial Sturdee and MacLennan

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