6.4 HORMONE THERAPY PROTECTS AGAINST DIABETES MELLITUS InthisstudywefoundthatHTusesignificantlydecreasedtheriskofdevelopingDMin postmenopausalwomen.TheriskofDMwasattenuatedby69%inwomenwhousedHT formorethanhalfofthe5yearfollowuptime.
Alimitationofourstudywasthatatbaseline,currentHTusershadfewerriskfactors forDMthanHTnonusers.However,adjustingforthesecharacteristicsdidnotaffectthe
results.Inaddition,nointeractionsbetweenHTuseandthesefactorswerefound.Inour study we did not distinguish between unopposed estrogen and combined therapy or between oral and transdermal application. According to the National Sickness Insurance organization, the criteria for reimbursement of medicines in DM included ICD9 codes 250.0–250.9andICD10codesE10–E14andE89.1andallthesecodeswereincludedunder the same SII code for DM (SVA 103). This code does not allow differentiation between T1DM and T2DM, but the age range of our population implies that incident cases consideredinouranalysisweremostlyT2DM.
Thisstudyareaisveryimportant,becausewomenwithDMhavea2to3foldriskof dying from acute myocardial infarction in comparison with diabetic men (Huxley et al.
2006).Thus,thebeneficialeffectofHTonDMcouldbetranslatedinthelongtermintoa beneficialeffectonmortality.
Several observational studies and RCTs (Manson et al. 1992, Kanaya et al. 2003, Margolisetal.2004,Bondsetal.2006,deLauzonGuillainetal.2009)haveconcernedthe roleofHTinthepreventionofDMbutnoneofthemhaverevealedasstrongapreventive effectasthatfoundinourstudy.TheNurses’HealthStudy(Mansonetal.1992)revealeda 20%lowerincidenceofDMinwomenusingHTcomparedwithwomenwhodidnot.Ina randomized controlled trial, the HERS study (Kanaya et al. 2003), the corresponding decreasewas35%.TheWomen’sHealthInitiativetrialrevealedan11–17%lowerriskof DM in HT users compared with nonusers (Margolis et al. 2004, Bonds et al. 2006). The WHI trial further showed a significant fall in insulin resistance during the first year of followupinwomentreatedwithcombinedHTorestrogenalone.Ontheotherhand,in theStrongHeartStudy(Zhangetal.2002)itwasreportedthattheriskofT2DMincreased by10%peryearofcurrentestrogenuse,whileGabaletal.(Gabaletal.1997)didnotfinda statisticallysignificantchangeinDMriskrelatedtoHTuse.Thelatestprospectivestudy, fromFrance(deLauzonGuillainetal.2009),revealedan18%lowerriskofnewonsetDM among postmenopausal women who had ever used HT compared with those who had never used it. Adjustment for BMI during followup did not substantially modify this association.Theinvestigatorsalsofoundthatanoralrouteofestrogenadministrationwas associatedwithagreaterdecreaseinDMriskthanapercutaneousroute.Whentakinginto account the type of progestagen in combined HT, only percutaneous estrogen combined withprogesterone,ororalestrogencombinedwithcyproteroneacetateornorethisterone acetate were significantly associated with a lower risk of DM, although there was no statistically significant heterogeneity between progestagens with regard to diabetes risk (de LauzonGuillain et al. 2009). A metaanalysis concerning components of metabolic syndrome, which included 107 randomized controlled trials of at least 8 weeks duration showed similarly that HT reduced the risk of newonset DM (by 30%) (Salpeter et al.
2006b).
Unlike these studies, in our study in postmenopausal women, DM risk reduction related to current HT use during followup was remarkable compared with never users.
ThegreatmajorityofthesewomenwhohadusedHTduringfollowupinourstudyhad startedHTbeforethebaseline.ThislongtermHTexposuremaypartlyexplaintheresults ofourstudy.WomenwhousedHTonlyinthepastandwhomayhavestoppedusebefore
followupmayhavelostpartofitsbenefit,whereaswomenwhousedHTforonlyashort timemaynothavegaineditsfullbenefit.InourstudyDMriskreductionwas19%forpast HTusers,althoughthisreductionwasnotstatisticallysignificant.
Impairedglucosetoleranceandinsulinresistanceareknowntoincreasewithage(Iozzo et al. 1999) but it is still unclear if menopauseper se modifies these increases (Bentley Lewisetal.2007).Comparedwithpremenopausalwomen,postmenopausalwomenhave similarglucoseandinsulinlevelsandarelativelyminordeteriorationinglucosetolerance, but they have increased insulin resistance, produce less insulin and clear it more slowly (Godsland2005).Thesechanges,alongwithdyslipidemiaandhypertension,areconsistent withmetabolicsyndromeandpredictT2DM(Lorenzoetal.2003)andCHD(Rewersetal.
2004) in postmenopausal women. The results of several studies indicate that ET may attenuate the accumulation of central fat in postmenopausal women (Gambacciani et al.
1997, Davis et al. 2000, Gambacciani et al. 2001, Sorensen et al. 2001) and this was also reported in the metaanalysis (Salpeter et al. 2006b), where HT use was found to be associated with an increase in lean body mass and a decrease in abdominal fat, which couldpartiallyexplainthereducedriskofDMinHTusers.HTcanhavefavorableeffects on body fat distribution and could, therefore, act to reduce DM risk via this mechanism (Godsland 2005). In the E3N study DM risk reduction was not found to be mediated by changesinBMI(deLauzonGuillainetal.2009).InourstudyBMIdidnotinteractwithHT use.InaCochraneDatabaseSystematicReview(Kongnyuyetal.2010)itwasconcluded thattherewasnoevidenceforaBMIchangeaccordingtoHTusethatwasdifferentfrom that normally experienced at the time of menopause. In the PEPI trial (Espeland et al.
1997), less weight gain or increase in waist and hip circumferences were registered in women who received EP therapy versus placebo. Similarly, in the Danish osteoporosis preventionstudy(Jensenetal.2003),HTuseseemedtohaveaweightreducingeffect.In the Heart and Estrogen/Progestin Replacement Study (HERS) (Kanaya et al. 2003), hormone therapy was associated with a significant decrease in waist circumference, but this change did not mediate the effect on HT on DM risk. In our study (and in the E3N study) we were not able to assess changes in abdominal fat or lean mass that could be inducedbyHT.
There are several mechanisms other than effects on adipose tissue and body fat distributionbywhichHTmaybeprotectiveagainstDM.Inaprospectivestudyofolder women not using HT, endogenous levels of bioavailable E2 and testosterone were positively associated with levels of fasting glucose, insulin, and estimated insulin resistance,whereasonlybioavailabletestosteronepositivelypredictedincidentDM(Ohet al. 2002). Positive associations between bioavailable E2 and testosterone with insulin resistancehavealsobeenobservedinacrosssectionalstudyofuntreatedpostmenopausal women (Kalish et al. 2003). Low levels of sex hormonebinding globulin are related negativelytoobesity,insulinresistance,andincidenceofDMinpostmenopausalwomen (Lindstedt et al. 1991, Haffner et al. 1992, Haffner et al. 1993). Hyperandrogenicity in womeniscloselyassociatedwithinsulinresistanceandriskfactorsofCVDandT2DM.
The processes underlying the changes in glucose and insulin levels with exposure to estrogen are not fully understood, but several mechanisms have been hypothesized.
Estrogen may have a direct effect on secretion of insulin by the pancreas. Estrogen receptorsarepresentinpancreaticbetacells(SutterDub2002),andestrogenincreasesthe releaseofinsulininbetacellculturemodels(Nadaletal.2004).Incontrast, thereisalso evidencewhichshowsthatincubationofisolatedisletswithestrogen,evenfordurations employedwhenislethyperplasiahasbeendemonstratedinvivo,hasnoeffectoninsulin production(Costrini&Kalkhoff1971,Nielsen1984).
Women taking estrogen have increased circulating growth hormone levels (Maw &
Wynn1972),butthisisseenonlywithoraladministrationandisnotaccompaniedbyany increase in insulinlike growth factors (DawsonHughes et al. 1986). These changes in growthhormoneconcentrationsarenotrelatedtochangesinglucosemetabolism(Maw&
Wynn 1972), and insulinlike growth factor levels are unaffected by estrogens (Dawson Hughesetal.1986).Favorableeffectsofestrogenonthepancreasareapparentfollowing hypophysectomy (Godsland 2005). Growth hormone stimulates insulin secretion and DNAsynthesisinisolatedislets(Nielsen1982)andstimulationofbetacellreplicationby growthhormoneappearstobeindependentofinsulinlikegrowthfactors(Rabinovitchet al.1983).
Apossiblemechanismunderlyingtheeffectsofestrogensoninsulinsecretionconcerns estrogeninducedchangesinglycemiaandinsulinsensitivity.Themostconsistenteffects oforalcontraceptivesandestrogenreplacementtherapyarealoweringoffastingplasma glucose concentrations and worsening glucose tolerance (Godsland et al. 1990, The WritingGroupforthePEPITrial1995,Triusuetal.2000,Zhangetal.2002,Margolisetal.
2004). Basal levels of insulin are unchanged or reduced, whereas glucosestimulated insulin is enhanced. In humans, estrogen deficiency (resulting, for example, from ovariectomy or the menopause) is associated with a relatively minor deterioration in glucosetolerance,andincreasedinsulinresistance(Godsland1996).Physiologicalestrogen replacementisthenassociatedwithrecoveryfromtheseeffects.Thereisevidencetoshow thatglucagoninducedhyperglycemiaisdiminishedbyestrogens(Godsland2005).Ithas alsobeenshownthatovariectomyincreasesplasmaglucagonconcentrationsandenhances the hyperglycemic action of glucagon, and following ovariectomy, estrogen administration decreases the hyperglycemic action of glucagon (AhmedSorour & Bailey 1980). Following ovariectomy, estrogen administration decreases the hepatic portal vein insulin/glucagonratio(Mandouretal.1977).
TheresultsofthepresentprospectivecohortstudyindicatethatHTusereducestherisk ofDMinpostmenopausalwomen.FurtherinformationontheroleofHT,accordingtothe route,administrationanddoseinmodifyingtheriskofDMisneeded.
6.5 USE OF CALCIUM SUPPLEMENTS AND RISK OF CORONARY HEART