Blood pressure, diabetes and BMI in postmenopausal women on HRT

Transcription

1 13 Bld pressure, diabetes and BMI in pstmenpausal wmen n HRT As the age-related incidence f cardivascular disease (CVD) in wmen accelerates after 50 years, it was suggested that menpause, with the accmpanying estrgen decline, was respnsible fr the suppressin f the prtectin seen usually in wmen. Cnsequently, several epidemilgical studies have been cnducted t assess the beneficial impact f estrgen supplements n cardivascular disease in pstmenpausal wmen. A meta-analysis has demnstrated that pstmenpausal estrgen therapy may result in a 50 % reductin in crnary heart disease (Stampfer and Clditz, 1991). Hrmne replacement therapy (HRT) seems t favrably influence the lipid and lipprtein prfile. Hwever, the cardiprtective effects f HRT appear t be multifactrial, as the effects n lipid metablism may accunt fr nly 25 t 30 % f the benefit. Menpause culd have detrimental effects n interrelated cardivascular risk factrs (bdy-fat distributin, bld pressure, glucse and insulin metablism) and HRT may affect many f these factrs. Thus, later studies examined these ptential mechanisms. In rder t reduce the risk f endmetrial cancer ptentially induced by estrgens alne, cmbined prgestgens have been prescribed fr several years. But bth these sterid hrmnes have metablic effects. Their influence n the cardivascular system is nt well knwn. In additin, their effects may depend n the type f sterid, the dse and rute f administratin. The purpse f this chapter was t assess the effect f HRT n glucse and insulin metablism, as well as n bld pressure, weight and bdy-fat distributin. Anther fcus was the influence f HRT in wmen with disturbances in these risk factrs, such as diabetic r hypertensive wmen. Observatinal studies have the limitatin f a treatment selectin bias. Wmen wh are taking pstmenpausal HRT tend t be healthier, better educated and mre cmpliant with lifestyle mdificatins reducing the cardivascular risk (Derby et al., 1995 ; Matthews et al., 1996). Mrever, the decisin t treat may well depend n a wman's cardivascular risk prfile. Finally, these studies ften classified wmen as estrgen users r nnusers, and smetimes a past-user grup was added. But mst did nt prvide a 195

2 Hrmne replacement therapy. Influence n cardivascular risk descriptin f the hrmnes used. As a cnsequence, these studies can nly be used t reinfrce the cnsistency f available results. Undubtedly, the best way t assess the effect f HRT n cardivascular risk factrs is in prspective randmized placeb-cntrlled trials. At present, this kind f study is rare. Despite their disavantage because f the absence f placeb grup, crss-ver studies, cmparing active treatments given in a randm sequence t the same wmen, may partly cmpensate fr this lack. Hwever, the number f clinical trials as well as the number f wmen included are insufficient given the variety f available treatments. The mst recent reprts n glucse and insulin metablism, bld pressure, weight and bdy-fat distributin were specially selected. Special attentin was given t clinical trials but epidemilgical studies are als reprted in the tables. Diabetes, glucse and insulin metablism The results f clinical trials are reprted n table Althugh subcutaneus implants f 25 r 50 mg 17 - estradil failed t imprve glucse metablism in surgically pstmenpausal wmen (Ntelvitz et al, 1987), ral estrgen replacement therapy may imprve glucse levels in pstmenpausai wmen (Cagnacci et al, 1992). These results are cnsistent with thse f the Pstmenpausal Estrgen/Prgestin Interventins (PEPI) Trial, which remains the best study because f the number f subjects and methdlgy (3-year fllw-up, randmized, duble-blind, placeb-cntrlled). As cmpared with placeb, all actively treated grups had an increase in pstchallenge glucse levels and a decrease in fasting glucse (PEPI, 1995). Oral cnjugated equine estrgen (CE) seem t have a dse-dependent effect n insulin sensitivity with an ameliratin f 25 % at the lwest dse (0.625 mg) but a deteriratin f 25 % at the 1.25 mg dse (Lindheim et al, 1993 ). In additin, when cmparing the effects f ral cnjugated equine estrgens and transdermal estradil after 3-mnth cntinuus administratin, it seemed that transdermal treatment had a mre beneficial effect n glucse metablism. It reduced fasting insulin levels and imprved the glucse-stimulated insulin respnse, as well as hepatic insulin clearance, whereas CE nly decreased fasting glucse levels (Cagnacci et al, 1992). Tw ther investigatrs studied the effect f estrgen substitutin n insulin sensitivity in relatin t the administratin rute. They included respectively 22 and 9 pstmenpausal wmen in clinical studies. In an insulin tlerance test, the first fund that transdermal estradil imprved insulin sensitivity as cmpared t ral equine estrgens, despite the cmparable estrgenicity f the respective 196 dses (Lindheim, 1994). This beneficial effect f transdermal treatment was

3 Ntelvitz et al. (1987) 6-mnth randmized 12 SurMp Randm HRT grup: n differences in carbhydrate and insulin metabstudy (hysterectmy + bilat. 25 r 50 mg E2 subcutaneus implants Iism phrectmy) Cagnacci et al. (1992) 3-mnth crss-ver 30 NatMp fr 2: 2 Y ln randm sequence E2T:... in mean fasting insulin levels +,1f pancrestudy mean age 53 cntinuus transderm. E z T r ral CE atic islet respnse t glucse challenge free f medicatins fr at mg ral CE :... in mean fasting glucse levels least 1 year Gdsland et al. (1993) 18-mnth randmized 61 healthy Caucasian Randm HRT grup: Oral HRT grup: deteriratin in glucse tlerance study Nat pstmp with HRT 1- cnt. ral CE mg + seq. ral and ve rail,1f in insulin secretin UK 29 Mp withut HRT dl-ng Transd. HRT grup: n significant changes in glurange f age? 2- E z T + transdermal nrethindrne cse r insulin metablism n medicatins acetate 3-Withut HRT Lindheim et al. (1993) 2-mnth randmized 15 healthy pstmp Randm HRT grup: Imprved insulin sensitivity with CE mg study 47 t 62 years - 9 premp 1-CE 0,625 mg (+25 %) 22 t 41 years - n HRT r 2-CE 0,625 mg + prgestin Altered insulin sensitivity (-25 %) with CE 1,25mg medicatin > 4 weeks 3-CE 1,25 mg and prgestin (-17 %) Lindheim et al. (1994) 2-mnth study 22 healthy Hispanic pstmp Randm HRT grup: Imprved insulin sensitivity with transdermal E z years 1- EzT (n=7) alne free f medicatins fr at 2- EzT + MPA (n=7) Delayed insulin clearance with E z + MPA r with CE ieast 4 weeks Other grup: 3-CE 1.25 mg (n=8) PEPI (1995) 3-year (since ), Cmmunity-based sampie f Randm HRT grup,1f in 2h-glucse levels (++ fr CE and MPA grups) multicenter, rand- 875 healthy pstmp 1-Placeb and... in fasting glucse (++ CE alne) in ail active mized, duble blind, years 2-CE treatment grups vs placeb placeb-cntrlled trial 3-CE+cyclic MPA 4-CE+cnt. MPA 5-CE+cyclic MP D'Sullivan and HO 6-mnth randmized, 9 healthy pstmp Randm HRT grup: Lwer... in nnesterified free fatty acid levels fr CE (1995) crss-ver study mean age E T Australia free f medicatins fr at 2-d1.25 mg least 2 mnths ANALYSIS t:d 0' 0- '1::1... (l> CI> CI>.!" 0- g: (l>... (l> CI> 0-5' '1::1 g(l> I:l,g êci> e:.. >-3 Table 13.1 : Glucse, insulin metablism and HRT in c1inical trials Authrs Study Design Study Ppulatin HRT Results >-' \0 -.]

4 Hrmne replacement therapy. Influence n cardivascular risk cnfirmed in terms f imprved insulin actin n lipid metablism (O'Sullivan and H, 1995). In a randmized study including 61 healthy pstmenpausal wmen in the United Kingdm, n changes in glucse r insulin levels were bserved with transdermal therapy. As fr ral therapy, it caused a deteriratin in glucse tlerance and an verall increase in insulin levels because f a reductin in insulin respnse t glucse, as estimated by an intravenus glucse tlerance test. Nne f the estrgen treatments caused insulin resistance but during the cmbined treatment (CE + the andrgenic prgestgen levnrgestrel), a deteriratin f glucse tlerance was bserved with alteratins f insulin secretin and develpment f insulin resistance (Gdsland et al., 1993). Similarly, the additin f medrxyprgesterne acetate (MPA) t the estradil treatment reversed the beneficial effects f percutaneus treatment and altered the clearance f insulin (Lindheim et al., 1994). In bservatinal studies (table 13.II), crss-sectinal cmparisns generally shwed lwer mean fasting insulin and/r glucse levels in pstmenpausal WOIT.en taking estrgens at the time f the study, with r withut prgestins, than in nn treated pstmenpausal wmen (Barrett-Cnnr and Laask, 1990; Manli et al., 1993 ; Nabulsi et al., 1993 ; Ferrara et al., 1995 ; Dallngeville et al., 1995). Only MPA was shwn t reverse the prtective effect f cnjugated estrgens (Barrett-Cnnr and Laask, 1990). Estrgen therapy succeeded in cunteracting the detrimental effects n glucse and insulin metablism which ccurred with thiazide diuretics in hypertensive pstmenpausal wmen (Saxman et al., 1994). Table 13.III summarizes studies n diabetes and HRT. A reprt f the Nurse's Health Study, invlving mre than wmen free f disease at entry, shwed that the 12-year incidence f diabetes was significantly reduced (RR=0.8) in current users f estrgens as cmpared with never users (Mansn et al., 1992). As fr HRT use in diabetic wmen, the data f a large crss-sectinal American study shwed that current use f estrgens resulted in a higher increase in triglycerides and HDL-chlesterl levels in diabetic than in nn diabetic pstmenpausal wmen. Mrever, this negative effect was mre prnunced in users f estrgen alne than f cmbined HRT (Rbinsn et al., 1996). Accrding t a randmized cntrlled study, the cmbinatin f percutaneus 17 - estradil and natural prgesterne did nt alter systlic and diastlic bld pressure in nn insulin-dependent diabetics after 6 mnths f treatment (Msnier-Pudar et al., 1991). Using an euglycemic hyperinsulinemic glucse clamp methd in a randmized, duble blind, crss-ver study, the administratin f 17- estradil t 25 pstmenpausal wmen with NIDDM imprved their glucse hmestasis (decrease fasting glucse, increase glucse disappearance, p=0.10) after estrgen substitutin but there was a slight 198 increase in bdy fat and bdy weight (Andersn et al., 1997).

5 Barrett-Cnnr Crss-sectinal 469 nndiabetic pstmp wmen Current use Lwer mean fasting insulin level in estrand Laaks (1990) ( ) years - Estrgen nnusers gens users vs nnusers (+ fasting glucse The Ranch Bernard Study - Premarin (CE) in CE grup) - Premarin (CE) + But n differences in HRT grup Prvera (MPA) Manli et al. Crss-sectinal Randm sample f Health Care Iists - Current use f estrgens Lwer mean levels f fasting insulin and (1993) The Cardivascular Health 2955 (alne r cmbined) glucse fr current users vs nn users Study 265 years - Past use/- Never used Nabulsi et al. Crss-sectinal pstmp frm 4 multiracial ppu- Current, frmer r past users Lwer mean fasting insulin and glucse (1993) ( ) latins f HRT levels in estrgen current users vs nn The Athersclersis years Fr current use, users Risk in Cmmunities Study estrgens r estrgens plus But n differences between alne estrgens prgestins and cmbined HRT Saxman et al. Crss-sectinal Ppulatin-based sampie Current use f estrgen (yes/ Estrgen users vs n medicatins (1994) The Ranch Bernard Study white pstmp n) with r withut prgestins lwer fasting glucse years - free f diabetes estrgen use reversed deleterius effect f users and nnusers f thiazide diuret- thiazide n fasting glucse and insulin but ics n imprved means fr 2h-glucse and insulin Ferrara et al. Crss-sectinal Ppulatin-based sample Current use f estrgens Lwer mean fasting insulin levels in (1995) ( ) 849 W (35 pstmp) - mean age 68 estrgens users than nn users The Ranch Bernard Study free f knwn diabetes Ais lwer fasting glucse Dallngeville et al. Crss-sectinal Vlunteers fr a standard check-up Current use Lwer mean fasting glucse levels in HRT (1995) ( ) pstmp Cmbined estrgen and pr- users France years gestin nly N gyneclgical surgery... \0 \0 ANALYSIS tp 0' 0.. ":l... '" en en >::!il 0.. '"ft en l tp é S ":l g I:l.g '" êen e:.. :;; I:l Table : Glucse, insulin metablism and HRT in bservatinal studies Authrs Study Design Study Ppulatin HRT Results

6 f(> "0 (> 8 (> :::... & ] ;e: ê: (>,., CI>,., ::!. CI> :>;" N Table : Diabetes and HRT Authrs Study Design Msnier-Pudar et al. 6-mnth randmized, cntrlled study (1991) France Mansn et al. (1992) Prspective (12-year fllw-up) The Nurses Health Study Rbinsn et al. (1996) Anderssn et al. (1997) Crss-sectinal ( ) The Athersclersis Risk in Cmmunities Study 3-mnth randmized, duble-blind, placeb-cntrlled crss-ver study Sweden Study Ppulatin 32 pstmp with NIDDM years n HRT fr at least 1 mnth pstmp years free f diabetes, CVD and cancer at entry 694 diabetic; nndiabetic pstmp wmen frm 4 multiracial ppulatins years 21 NatMp and 4 SurMp pstmp with NIDDM HRT Randm HRT grup: 1-E 2 T + natural prgesterne 2-n treatment Current, frmer r past users f HRT Results N variatins in bdyweight, SBP and DBP in either grup - Current use f estrgens Incidence f diabetes (alne r cmbined) RR=0,80 fr current vs never users - Past use - Never used Fr current use, estrgens r estrgens plus prgestins Active treatment : E2 + nrethisterne acetate higher triglycerides and lwer HDL increase fr estrgen users in diabetics than in nndiabetics higher triglycerides levels in alne estrgen users than cmbined HRT users diabetics Decrease in mean fasting glucse (-2.6 mml/i) Slight increase in mean bdyweight (+1.3 kg) and bdyfat (+0.4 kg)

7 Bld pressure, diabetes and BMI in pstmenpausal wmen n HRT Bld pressure and hypertensin In clinical trials (table 13.IV), ail the randmized studies shwed n significant changes in mean SBP r DBP after estrgen treatment. The type f estrgen, the rute f administratin and cmbinatin with a prgestin did nt alter these results. The three bservatinal studies reprted are crss-sectinal (table 13.V). They gave cntrversial results. In a cmmunity-based sample frm the Ranch Bernard chrt, the mean SBP was lwer in wmen treated by bth cnjugated estrgens and MPA as cmpared with estrgen nnusers. The statistically nn significant difference bserved fr estrgen alne was attributed t a lack f pwer (Barrett-Cnnr et a1., 1989). Fr the vlunteers in France, wmen wh tak cmbined estrgens and prgestins had lwer mean SBP and DBP, even after adjustment fr cnfunders such as age, bdy-mass index, smking, alchl intake, exercise status, parity (Dallngeville et a1., 1995). In cntrast, n differences in SBP r DBP were bserved in a large sample f middle-aged wmen frm fur multiracial American ppulatins (Nabulsi et a1., 1993). Obesity and bdy-fat distributin Amng the clinical studies (table 13.VI), a 3-mnth crss-ver study with transdermal estradil r cnjugated equine estrgens shwed that neither treatment had an effect n BMI in a sample f 30 wmen in natural menpause fr mre than 2 years (Cagnacci et a1., 1992). N changes were bserved with estradil valerate in a 15-mnth study (Utian, 1978) r with estradil plus nmgestrl acetate in a French randmized piaceb-cntrlled trial (Cnard et a1., 1995). A 2-year, randmized, blinded, piaceb-cntrlled study assessed the re1atinships f HRT with bdy-fat distributin (Dual-Energy X-ray Absrptimetry) rather than verall besity. Estradil valerate, cmbined with CPA r LNG, prevented the increase in abdminal fat bserved in the nn treated grup (Haarb et a1., 1991). FinaIly, in the PEPI trial there was an increase in bth weight and WHR in ail grups, which was significantly higher n the placeb than n estrgen alne (PEPI, 1995). Amng the fur epidemilgical studies reprted (table 13.VII), three fcused n pstmenpausal wmen and the mst recent was prspective. Their results were cnsistent: wmen wh were current estrgen users at the time f the studies had a lwer mean BMI as cmpared with nnusers, after adjustment fr age. This assciatin was nt affected by additinal prgestin 201

8 r '",g '"8 ::l... '" 9- ] ':'i F '" ('l a.. en ('l ::!. en ;.;-' N N Table B.lV : Bld pressure and HRT in c1inical trials Authrs Study Design Study Ppulatin HRT Results Utian, 1978 Prspective (15-mnth fllw-up) 50 healthy white SurMp (hysterectmy + bilai. phrectmy) years Sequence: 6 mnth E2V (2x3mnth) 3 mnths placeb 3 mnths CE N significant changes in DBP n any frm f treatment Ntelvitz et al. (1987) Prspective (6 mnths) randmized study 12 SurMp (hysterectmy + bilai. phrectmy) Randm HRT grup: 25 r 50 mg E2 subcutaneus implants N differences in SBP and DBP PEPI (1995) 3-year (since ), multicenter, randmized, duble blind, placebcntrlled trial Cmmunity-based sampie f 875 healthy pstmp years Randm HRT grup G1-Placeb G2-CE G3-CE+cyclic MPA G4-CE+cnl. MPA G5-CE+cyclic MP N differences in change between grups fr the mean SBP and DBP Table B.V : Bld pressure and HRT in bservatinal studies Authrs Barrett-Cnnr et al. (1989) Nabulsi et al. (1993) Dallngeville et al. (1995) Study Design Study Ppulatin HRT Results Crss-sectinal Upper middle-class cmmunity Current use Lwer mean SBP and DBP fr CE+MPA grup ( ) pstmp - Estrgen nnusers vs nnusers The Ranch Bernard Study years - Premarin (CE) N differences between CE and CE+MPA - Premarin (CE) + grups Prvera (MPA) Crss-sectinal pstmp frm 4 multiracial Current, frmer r past N differences in mean SBP and DBP ( ) ppulatins users f HRT between estrgen current users vs nnusers The Athersclersis years Fr current use, N differences CE vs nn users Risk in Cmmunities Study estrgens r estrgens Neither between estrgens alne and plus prgestins cmbined HRT Crss-sectinal Vlunteers fr a standard Current use Lwer mean SBP and DBP in HRT users ( ) check-up Cmbined estrgen and France pstmp prgestin nly years N gyneclgical surgery

9 Utian, mnth study 50 healthy White Sequence: N significant changes in bdyweight n surgically Mp 6 mnths E2V (2x3mnths) any frm f treatment (hysterectmy + bilai. phrectmy) 3 mnths placeb years 3 mnths CE Harrb et al. (1991) 2-year, randmized, blind, pla- 62 healthy Danish pstmp wmen fr at least Randm HRT grup DEXA measurements ceb-cntrlled study 6 mnths G1-Placeb Cmbined estrgen-prgestin therapy years G2-E 2 V+ CPA prevented the increase in abdminal fat n diseases and n medicatins G2-E 2 V+ LNG Cagnacci et al. (1992) 3-mnth crss-ver study 30 wmen in natural menpause fr 2 Y ln randm sequence N changes in BMI after estrgen mean age 53 cntinuus transderm. administratin (bath grups) free f medicatins fr at least 1 year transdermal E 2 r ral CE Cnard et al. (1995) Randmized, duble-blind, 57 healthy naturally menpausal wmen Randm grup N significant changes in weight placeb-cntrlled prspective mean age 52 G1 - Placeb trial free f medicatins fr at least 2 mnths G2 - nmgestrl acetate France E 2 G2 - nmgestrl acetate E 2 PEPI (1995) 3-year (since ), Cmmunity-based sample f 875 healthy Randm HRT grup Increase in weight and WHR fr ail grups multicenter, randmized, pstmp G1-Placeb (weight ++ Placeb vs CE alne) duble blind, placeb years G2-CE cntrlled trial G3-CE+cyclic MPA G4-CE+cnt. MPA G5-CE+cyclic MP ANALYSIS t:d 0' 0- '"... (l> en en id (l>... (l> en 0- S' '" g(l> =::.g êen e:.. 8(l> =:: =:: Table n.vl : Bdy weight, bdy-fat distributin and HRT in c1inical trials Authrs Study Design Study Ppulatin HRT Results N VJ

10 Results fr wmen years lwer mean BMI in estrgens users Lwer mean BMI in bth CE, CE+MPA and past-users grup vs nn users Lwer mean BMI and WHR fr current users vs nn users Lwer mean BMI at baseline fr cntinuus users vs never users But n differences in change f BMI during the fllw-up f... :i 'l:l p.-....f:l ;e: S" " ::: Cl ll' ë-: if> Cl Ë.. el ::!. if> i'<' N ọ.j>. Table 13.VII Bdy weight, bdy-fat distributin and HRT in bservatinal trials Authrs Study Design Study Ppulatin HRT Wallace et al. (1987) Crss-sectinal The Lipid Research Clinics Prgram Prevalence Study Randm samples f 10 Nrth American White ppulatins years Reprted current estrgen use (yes/n) Barrett-Cnnr et al. (1989) Crss-sectinal ( ) The Ranch Bernard Study Upper middle-class cmmunity pstmp years Current use - Estrgen nn users (past+never) - Premarin (CE) - Premarin (CE) + Prvera (MPA) Manli et al. (1993) Crss-sectinal The Cardivascular Health Study Randm sample f Health Care lists 2955 ::: 65 years - Never used - Past use - current use f estrgens (alne r cmbined) Kritz-Silversteinand Barrett Cnnr (1996) Prspective (15-year fllw-up) The Ranch-Bernard Study Upper middle-class cmmunlty 671 pstmp W years at entry use fr the 15 years - estrgen never used - intermittent use - cntinuus use

11 Bld pressure, diabetes and BMI in pstmenpausal wmen n HRT use (Barrett-Cnnr et a1., 1989). In the Cardivascular Health Study, current users als had lwer central adipsity, as measured by the Waistt-Hip Rati (Manli et a1., 1993). As cncerns lngitudinal data, after a 15-year fllw-up f 671 pstmenpausai wmen ver 65 years at entry, there were n differences in BMI changes between wmen wh were cntinuus estrgen users, intermittent users r never users (Kritz-Silverstein et Barrett-Cnnr, 1996). Critical analysis Clinical studies suggest that transdermal 17 -estradil has a beneficial effect n glucse metablism decreasing fasting insulin levels and increasing hepatic insulin clearance (Cagnacci et a1., 1992). In cntrast, the effect f ral CE culd be dse-dependent : high dses may have detrimental effects n carbhydrate metablism (Lindheim et a1., 1993). Oral preparatins result in high sterid cncentratins in the liver, the majr site f insulin prcessing and actin. Thus, it is pssible that the transdermal rute culd be mre favurable than the ral rute as regards insulin and glucse metablism, because f a lesser impact n the liver. In additin, prgestgens may prduce adverse effects n glucse and insulin metablism. In a randmized placeb-cntrlled trial, the cmbinatin f transdermal 17-estradiI with nrethisterne acetate had n effects n carbhydrate metablism (GdsIand et a1., 1993). Mrever, the cmbined ral CE/nrgestrel phase f treatment, cmpared with estrgen alne, was assciated with a deteriratin f glucse tlerance, an increase in insulin resistance and alteratins f insulin secretin (Gdsland et a1., 1993). Further studies are needed t assess whether the use f less andrgenic prgestgens cuid avid these negative changes. There is n evidence f an increased incidence f diabetes in wmen n HRT (Mansn et a1., 1992). Hwever, srne lipid and lipprtein disturbances have been bserved in diabetic users f estrgen replacement therapy (Rbinsn et a1., 1996). The changes in terms f weight (Andersn et a1., 1997) and bld pressure (Msnier-Pudar et a1., 1991) were small r absent, and their imprtance is unknwn. A decade ag, Maschkak et Lb (1985) reviewed epidemilgical and clinical studies assessing pstmenpausal estrgens, with r withut added prgestgens, in relatin t SBP and DBP. Few studies have since been cnducted. Accrding t the mst carefully designed studies, bld pressure des nt change with estrgen therapy in nrmtensive subjects (Utian, 1978; Ntelvitz et a1., 1987; PEPI, 1995). Cnsequently, the psitive reiatinships bserved in srne crss-sectinal studies may be due t the pretreatment 205

12 Hrmne replacement therapy. Influence n cardivascular risk characteristics f pstmenpausal wmen. In additin, the ptential reductin in bld pressure is perhaps nt sufficient t have a marked clinical effect n the deve10pment f athersclersis. As fr hypertensive pstmenpausal wmen, Bealeet Cllins (1996) nted that ne study fund n effect f HRT n bld pressure in patients with hypertensin. Hwever, because f the lack f randmized placeb cntrlled studies, n cnclusins can be drawn cncerning an assciatin between HRT and hypertensin. The results cncerning the impact f HRT n weight differ accrding t the type f studies. The lwer mean BMI bserved in current estrgen users in bservatinal studies may be attributed t their better cardivascular prfile at baseline. As regards clinical trials, HRT des nt nrmally cause a significant increase in weight r in BMI (Utian, 1978; Cagnacci et a1., 1992; Cnard et a1., 1995; PEPI, 1995). Weight increases with age. In cntrast, replacement hrmnes after menpause may imprve the redistributin f fat by limiting the andrid pattern (Haarb et a1., 1991). This bservatin may be f imprtance since central fat is assciated with ther adverse metablic changes, such as increased triglyceridemia, bld pressure and insulin resistance, as well as decreased HDL-chlesterlemia. T 0 cnc1ude, the favurable impact f HRT n carbhydrate metablism may depend n the estrgen prducts, the dse, the rute f administratin and n the andrgenicity f the added prgestgen. The studies invlving estrgen and bld pressure shwed slight decreases r n changes in bld pressure. HRT may prevent the athergenic bdy-fat distributin (andrid) which ccurs after menpause. Hwever, fr diabetic wmen, the use f HRT needs t be fully weighed up. Finally, it is imprtant t remember that mst studies have been cnducted in the United States where the cardivascular risk and the estrgen/prgestgen prducts are different frm in France. Thus, the benefit f HRT needs t be clearly established in the French cntext in a large randmized placeb-cntrlled study. BIBLIOGRAPHY ANDERSSON B, MATTSON LA, HAHN L, MARIN P et al. Estrgen Replacement therapy decreases hyperandrgenicity and imprves glucse hmestasis and plasma lipids in pstmenpausai wmen with NIDDM. J Clin Endcrinl Metab 1997, 82 : BARRETT CONNOR E, LAAKSO M. Ischemie heart disease risk in pstmenpausal wmen. Effects f estrgen use n glucse and insulin levels. Arterisclersis 1990, 10: BARRETT-CONNOR E, WINGARD DL, CRIQUI MH. Pstmenpausal estrgen use and heart disease risk factrs in the 1980s. Ranch Bernard, Calif, revisited. JAMA 1989, 261 :

13 B100d pressure, diabetes and BMI in pstmenpausa1 wmen n HRT BEALE CM, COLLINS P. The menpause and the cardivascular system. Baillieres Clin Obstet Gynaecl1996, 10: CAGNACCI A, SOLDANI R, CARRIERO PL, PAOLETTI AM et al. Effects f lw dses f transdermal 17 beta-estradil n carbhydrate metablism in pstmenpausal wmen. 1 Clin Endcrinl Metab 1992, 74: CONARD J, BASDEVANT A, THOMAS JL, OCHSENBEIN E et al. Cardivascular risk factrs and cmbined estrgen-prgestin replacement therapy: a placeb-cntrlled study with nmegestrl acetate and estradil. Fertil Steril 1995, 64 : DALLONGEVILLE J, MARECAUX N, ISOREZ D, ZYLBERGBERG G et al. Multiple crnary heart disease risk factrs are assciated with menpause and influenced by substitutive hrmnal therapy in a chrt f French wmen. Athersclersis 1995, 118 : DERBY CA, HUME AL, MCPHILLIPS JB, BARBOUR MM, CARLETON RA. Prir and current health characteristics f pstmenpausal estrgen replacement therapy users cmpared with nnusers. Am 1 Obstet Gynec11995, 173: FERRARA A, BARRETT-CONNOR E, WINGARD DL, EDELSTEIN SL. Sex differences in insulin levels in lder adults and the effect f bdy size, estrgen replacement therapy, and glucse Tlerance status. The Ranch Bernard Study, Diabetes Care 1995,18: GODSLAND IF, GANGAR K, WALTON C, CUST MP et al. 1nsulin resistance, secretin, and eliminatin in pstmenpausal wmen receiving ral r transdermal hrmne replacement therapy. Metablism 1993,42 : HAARBO J, MARSLEW U, GOTFREDSEN A, CHRISTIANSEN C. Pstmenpausal hrmne replacement therapy prevents central distributin f bdy fat after menpause. Metablism 1991,40: KRITZ-SILVERSTEIN D, BARRETT-CONNOR E. Lng-term pstmenpausal hrmne use, besity, and fat distributin in lder wmen. lama 1996, 275 : LINDHEIM SR, PRESSER SC, DITKOFF EC, VIJOD MA et al. A pssible bimdal effect f estrgen n insulin sensitivity in pstmenpausal wmen and the attenuated effect f added prgestin. Fertil Steril 1993, 60: LINDHEIM SR, DUFFY DM, KOJIMA T, VIJOD MA, STANCZYK FZ, LOBO RA. The rute f administratin influences the effect f estrgen n insulin sensitivity in pstmenpausa1 wmen. Fertil Steril 1994, 62 : MANOLIO TA, FURBERG CD, SHEMANSKI L, PSATY BM et al. Assciatins f pstmenpausal estrgen use with cardivascular disease and its risk factrs in lder wmen. The CHS Cllabrative Research Grup. Circulatin 1993, 88 : MANSON JE, RIMM EB, COLDITZ GA, WILLETT WC et al. A prspective study f pstmenpausai estrgen therapy and subsequent incidence f nn-insulin-dependent diabetes mellitus. Ann Epidemil 1992, 2 : MASCHKAK CA, LOBO RA. Estrgen replacement therapy and hypertensin. 1 Reprd Med 1985, 10 : MATTHEWS KA, KULLER LH, WING RR, MEILAHN EN et al. Prir t use estrgen replacement therapy, are users healthier than nnusers?am 1 Epidemil1996, 143: MOSNIER-PUDAR H, FAGUER B, GUYENNE TT, TCHOBROUTSKY G. Effets de la substitutin par 17 beta estradil percutané et prgestérne rale sur la pressin artérielle et les paramètres métabliques chez des patientes diabétiques nn insulindépendantes. Arch Mal Cœur 1991, 84: NABULSI AA, FOLSOM AR, WHITE A, PATSCH W et al. Assciatin f hrmne-replacement therapy with varius cardivascular risk factrs in pstmenpausal wmen. The Athersclersis Risk in Cmmunities Study Investigatrs. N Engl 1 Med 1993, 15 :

14 Hrmne replacement therapy. Influence n cardivascular risk NOTELOVITZ M, JOHNSTON M, SMITH S, KITCHENS C. Metablic and hrmnal effects f 25-mg and 50-mg 17 beta-estradil implants in surgically menpausal wmen. Obstet Gynecl 1987,70: O'SULLIVAN A, HO KKY. A cmparisn f the effects f ral and transdermal estrgen replacement n insulin sensitivity in pstmenpausal wmen. 1 Clin Enderinl Metab 1995, 80: PEPI. Effeets f estrgen r estrgen/prgestin regimens n heart disease risk factrs in pstmenpausal wmen. The Pstmenpausal Estrgen/Prgestin Interventins (PEPI) Trial. The Writing Grup fr the PEPI Trial. lama 1995, 273 : ROBINSON JC, FOLSOM AR, NABULSI AA, WATSON R et al. Can pstmenpausal hrmne replacement imprve plasma lipids in wmen with diabetes? The Athersclersis Risk in Cmmunities Study Investigatrs. Diabetes Care 1996, 19: SAXMAN KA, BARRETT-CONNOR EL, MORTON DJ. Thiazide-assciated metablic abnrmalities and estrgen replacement therapy: an epidemilgical analysis f pstmenpausal wmen in Ranch Bernard, Califrnia. 1 Clin Enderinl Metab 1994, 78: STAMPFER MJ & COLDITZ GA. Estrgen replacement therapy and crnary heart disease: a quantitative assessment f the epidemilgical evidence. Prev Med 1991, 20 : UTIAN WH. Effect f pstmenpausal estrgen therapy n diastlic bld pressure and bdyweight. Maturitas 1978, 1 : 3-8 WALLACE RB, HEISS G, BURROWS B, GRAVES K. Cntrasting diet and bdy mass amng users and nnusers f ral cntraceptives and exgenus estrgens : the Lipid Research Clinics Prgram Prevalence Study. Am 1 Epidemill987, 125 :