Shumaker SA, Legault C, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN 3rd, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J; WHIMS Investigators
JAMA. 2003 May 28;289(20):2651-62.

CONTEXT: Postmenopausal women have a greater risk than men of developing Alzheimer disease, but studies of the effects of estrogen therapy on Alzheimer disease have been inconsistent. On July 8, 2002, the study drugs, estrogen plus progestin, in the Women's Health Initiative (WHI) trial were discontinued because of certain increased health risks in women receiving combined hormone therapy.
OBJECTIVE: To evaluate the effect of estrogen plus progestin on the incidence of dementia and mild cognitive impairment compared with placebo.
DESIGN, SETTING, AND PARTICIPANTS: The Women's Health Initiative Memory Study (WHIMS), a randomized, double-blind, placebo-controlled clinical trial, began enrolling participants from the Women's Health Initiative (WHI) estrogen plus progestin trial in May 1996. Of the 4894 eligible participants of the WHI study, 4532 (92.6%) postmenopausal women free of probable dementia, aged 65 years or older, and recruited from 39 of 40 WHI clinical centers were enrolled in the WHIMS.
INTERVENTION: Participants received either 1 daily tablet of 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate (n = 2229), or a matching placebo (n = 2303). MAIN OUTCOME MEASURES: Incidence of probable dementia (primary outcome) and mild cognitive impairment (secondary outcome) were identified through a structured clinical assessment.
RESULTS: The mean (SD) time between the date of randomization into WHI and the last Modified Mini-Mental State Examination (3MSE) for all WHIMS participants was 4.05 (1.19) years. Overall, 61 women were diagnosed with probable dementia, 40 (66%) in the estrogen plus progestin group compared with 21 (34%) in the placebo group. The hazard ratio (HR) for probable dementia was 2.05 (95% confidence interval [CI], 1.21-3.48; 45 vs 22 per 10 000 person-years; P =.01). This increased risk would result in an additional 23 cases of dementia per 10 000 women per year. Alzheimer disease was the most common classification of dementia in both study groups. Treatment effects on mild cognitive impairment did not differ between groups (HR, 1.07; 95% CI, 0.74-1.55; 63 vs 59 cases per 10 000 person-years; P =.72).
CONCLUSIONS: Estrogen plus progestin therapy increased the risk for probable dementia in postmenopausal women aged 65 years or older. In addition, estrogen plus progestin therapy did not prevent mild cognitive impairment in these women. These findings, coupled with previously reported WHI data, support the conclusion that the risks of estrogen plus progestin outweigh the benefits.

Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, Gass ML, Stefanick ML, Lane DS, Hays J, Johnson KC, Coker LH, Dailey M, Bowen D; WHIMS Investigators.
JAMA. 2003 May 28;289(20):2663-72.

CONTEXT: Observational studies have suggested that postmenopausal hormone treatment may improve cognitive function, but data from randomized clinical trials have been sparse and inconclusive. The Women's Health Initiative Memory Study (WHIMS) is an ancillary study of the Women's Health Initiative (WHI) hormone therapy trials. On July 8, 2002, the estrogen plus progestin therapy in the WHI trial was discontinued because of certain increased health risks for women.
OBJECTIVE: To determine whether estrogen plus progestin therapy protects global cognitive function in older postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled clinical trial, WHIMS is an ancillary study of geographically diverse, community-dwelling women aged 65 years or older from 39 of 40 clinical centers within the WHI estrogen plus progestin trial that started in June 1995. Of 4894 eligible postmenopausal women aged 65 years or older and free of probable dementia at baseline, 4532 (92.6%) were enrolled in the estrogen plus progestin component of WHIMS. A total of 4381 participants (96.7%) provided at least 1 valid cognitive function score between June 1995 and July 8, 2002.
INTERVENTIONS: Participants received either 1 daily tablet containing 0.625 mg of conjugated equine estrogen with 2.5 mg of medroxyprogesterone acetate (n = 2145) or matching placebo (n = 2236).
MAIN OUTCOME MEASURE: Global cognitive function measured annually with the Modified Mini-Mental State Examination.
RESULTS: The Modified Mini-Mental State Examination mean total scores in both groups increased slightly over time (mean follow-up of 4.2 years). Women in the estrogen plus progestin group had smaller average increases in total scores compared with women receiving placebo (P =.03), but these differences were not clinically important. Removing women by censoring them after adjudicated dementia, mild cognitive impairment, or stroke, and nonadherence to study protocol, did not alter the findings. Prior hormone therapy use and duration of prior use did not affect the interpretation of the results, nor did timing of prior hormone therapy initiation with respect to the final menstrual period. More women in the estrogen plus progestin group had a substantial and clinically important decline (> or =2 SDs) in Modified Mini-Mental State Examination total score (6.7%) compared with the placebo group (4.8%) (P =.008).
CONCLUSIONS: Among postmenopausal women aged 65 years or older, estrogen plus progestin did not improve cognitive function when compared with placebo. While most women receiving estrogen plus progestin did not experience clinically relevant adverse effects on cognition compared with placebo, a small increased risk of clinically meaningful cognitive decline occurred in the estrogen plus progestin group

Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, Kotchen T, Curb JD, Black H, Rossouw JE, Aragaki A, Safford M, Stein E, Laowattana S, Mysiw WJ; WHI Investigators.
JAMA. 2003 May 28;289(20):2673-84.

CONTEXT: The Women's Health Initiative (WHI) trial of estrogen plus progestin was stopped early because of adverse effects, including an increased risk of stroke in the estrogen plus progestin group.
OBJECTIVE: To assess the effect of estrogen plus progestin on ischemic and hemorrhagic stroke and in subgroups, and to determine whether the effect of estrogen plus progestin was modified by baseline levels of blood biomarkers.
DESIGN: Multicenter double-blind, placebo-controlled, randomized clinical trial involving 16 608 women aged 50 through 79 years with an average follow-up of 5.6 years. Baseline levels of blood-based markers of inflammation, thrombosis, and lipid levels were measured in the first 140 centrally confirmed stroke cases and 513 controls.
INTERVENTIONS: Participants received 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate (n = 8506) or placebo (n = 8102).
MAIN OUTCOME MEASURES: Overall strokes and stroke subtype and severity were centrally adjudicated by stroke neurologists.
RESULTS: One hundred fifty-one patients (1.8%) in the estrogen plus progestin and 107 (1.3%) in the placebo groups had strokes. Overall 79.8% of strokes were ischemic. For combined ischemic and hemorrhagic strokes, the intention-to-treat hazard ratio (HR) for estrogen plus progestin vs placebo was 1.31 (95% confidence interval [CI], 1.02-1.68); with adjustment for adherence, the HR was 1.50 (95% CI, 1.08-2.08). The HR for ischemic stroke was 1.44 (95% CI, 1.09-1.90) and for hemorrhagic stroke, 0.82 (95% CI, 0.43-1.56). Point estimates of the HRs indicate that excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin. Other risk factors for stroke, including smoking, blood pressure, diabetes, lower use of vitamin C supplements, blood-based biomarkers of inflammation, higher white blood cell count, and higher hematocrit levels did not modify the effect of estrogen plus progestin on stroke risk.
CONCLUSIONS: Estrogen plus progestin increases the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to estrogen plus progestin appeared to be present in all subgroups of women examined.

Il Women's Health Initiative Study (WHI) continua a fornire informazioni negative sulla terapia estro-progestinica nelle donne in menopausa. Come si sa, lo studio è stato interrotto prematuramente perché la terapia ormonale sostitutiva aveva dimostrato di essere associata ad un aumento del rischio di malattie cardiache, ictus cerebrali, tromboembolismo venoso e tumore invasivo della mammella. Uno dei sottoprogetti dello studio era indirizzato alla valutazione dell'effetto della terapia ormonale sulla demenza e sulla funzione cognitiva nelle donne di età superiore ai 65 anni. Per la demenza, l'ipotesi di un effetto protettivo della terapia sostitutiva era basata su una serie di dati epidemiologici, in particolare, sull'elevato rischio delle donne in menopausa di sviluppare una Malattia di Alzheimer, e sugli effetti protettivi che gli estrogeni sembrano avere sul sistema nervoso (promozione dell'attività colinergica, riduzione della perdita neuronale, stimolo della crescita assonale e della formazione di spine dendritiche ecc.). A sostegno, la letteratura forniva una nutrita serie di studi osservazionali, riassunti in due recenti metanalisi, che suggerivano un effetto protettivo degli estrogeni nei confronti della demenza di Alzheimer. Vi erano dunque buoni elementi per sostenere che una terapia sostitutiva protratta potesse influire positivamente sull'incidenza della demenza nelle donne in menopausa. Meno forti erano i dati a supporto dell'ipotesi che la terapia sostitutiva potesse influire sul declino cognitivo, o per lo meno, i dati degli studi osservazionali e di intervento in favore degli estrogeni erano piuttosto inconsistenti. I risultati di questi due sottoprogetti del WHI sono quanto mai deludenti e, almeno per quanto riguarda l'incidenza della demenza, sono addirittura in contrasto con l'ipotesi iniziale. La terapia con estrogeni e progestinici ha infatti aumentato il rischio relativo di demenza del 34% e non ha avuto alcun effetto positivo sul declino cognitivo. Anzi, nelle donne del gruppo di trattamento è stato rilevato un modesto aumento del rischio di un significativo peggioramento della funzione cognitiva. In termini numerici è comunque poca cosa. Al di là della significatività statistica, l'aumento del rischio di demenza interesserebbe solo 23 donne su 10.000 per anno di trattamento. Quello che più colpisce è la negazione dell'ipotesi iniziale che sembrava ben supportata. Del resto, anche l'ipotesi di un effetto favorevole della terapia sostitutiva della menopausa sulla morbilità cardiovascolare era suffragata da importanti dati, ma HERS (JAMA 2002;288:49-57), ESPRIT (Lancet 2002;360:2001-2008), lo stesso WHI (JAMA 2002;288:321-333) l'hanno clamorosamente negata. Un'altra dura botta alla terapia sostitutiva viene anche da uno studio osservazionale danese, recentemente pubblicato sul British Medical Journal (numero del 22 febbraio 2003). In questo studio la terapia sostitutiva non ha avuto alcun effetto protettivo sulla malattia coronarica. Anzi, nelle donne diabetiche, si associava ad un eccesso di mortalità. Per la terapia sostitutiva della menopausa con estrogeni e progestinici sembra che la storia sia finita. La sua supposta azione protettiva nei confronti della malattia aterosclerotica è miseramente naufragata con la dimostrazione di un effetto o nullo o negativo sugli end points cardiaci e cerebrovascolari (come riconfermato proprio da una rivisitazione specifica dei risultati del WHI) ed è possibile che proprio un'azione negativa sul sistema arterioso cerebrale sia alla base dell'assenza di protezione nei confronti della demenza e del declino della funzione cognitiva. Ma questa è solo un'ipotesi. Il WHI e gli altri studi di intervento hanno messo una pietra tombale sulla terapia con estrogeni e progestinici nella menopausa? Forse sì. Orami sono in molti a ritenere che gli estrogeni ed i progestinici debbano essere usati solo per il controllo dei sintomi della menopausa, a dosi basse e per un periodo di tempo limitato.

Domenico Sommariva - Divisione di Medicina Interna 1, Ospedale G. Salvini, Garbagnate Milanese