Académie royale de Médecine de Belgique


Résumé de Andrea Genazzani, membre étranger

(Ont pris part à la discussion : MM. les Prs Cl. Saegerman, G. Fillet, J.E. Dumont et U. Gaspard).


par Andrea R. GENAZZANI (Université de Pise – Italie), membre étranger.                   

The last century was just ending and the general consent toward Hormone Replacement Therapy of the Menopause growed sustained by the general perception from the greatest part of scientific data that this therapy, in addition to the efficacy of the treatment of menopausal symptoms, have also a positive impact in the prevention of Cardiovascular diseases, the major cause of women mortality.

Some concern however were still present at that time for the negative impact on breast cancer with an increased relative risk which varied from treatment to treatment on the basis of the substances used, mainly the progestogens, and also on the basis of the way of administration of estrogens with the Oral route showing the greatest negative impact, while transdermal administration and the use of natural progesterone were not associated to any particular increase of the natural breast cancer risk.

This was the moment (J. Am. Med. Assoc. 2002; 288: 321–333) when the WHI study results were published… in the first version!

After that nothing remained the same: the media (TV, Journals, Magazines etc.) diffused the news that the Hormone Replacement Therapy represent a risk for Women’s Health, without any doubt that the WHI study represent the TRUTH !! 

The very important media impact and a great attention to media’s information, more than to the scientific data, were the major results of the WHI study.

This was evident since the moment when WHI study results were presented to the public at NIH in Bethesda during a two days meeting in September 2001.

In a full consensus environment with tenth of speakers showing data who stigmatize the role of Hormone replacement Therapy of the Menopause where the treatment (Conjugated Equine Estrogens 0,625 mg and Medroxy Progesterone Acetate 2,5 mg) given in comparison to placebo for more than 7 years apparently increased the Cardiovascular risk, the Breast Cancer risk, the Cerebrovascular risk, the Alzheimer disease risk.. in a population ranging from 50 to 79 years, where the Menopause symptomatic women were nearly totally excluded.

Only few persons at that meeting and in particular Sindney Shapiro, Epidemiologist, and myself , as Past President of the International Menopause Society, had official concerns regarding the study, the results the validity and their interpretation.

Sidney criticized the epidemiological design and lack of consideration of the very important movements inside to the groups of treated and controls and the lack of symptomatic individuals with an extraordinary number of aged person treated many years after the Menopause.

I presented my concern for the quality of treated individual, the exclusion of the symptomatic, the inclusion of aged population starting treatments many years after menopause, and the extraordinary abundance of overweight, obese patients and individuals with already existing cardiovascular diseases not properly treated.

Our comments were totally denied by the audience, who was more opened to accept without any criticism the immense flow of data presented by the WHI investigators.

In an editorial (Gynecol Endocrinol. 2002 Aug;16(4):255-7) that I wrote immediately after WHI study publication, I expressed my doubts on the validity of the study, as a study on the effect of Hormone Replacement Therapy for the treatment of the Menopause. The WHI in fact was showing the effects of a specific hormone association therapy (CEE plus MPA) in women starting the treatment from 50 to 79 year, for a period of more than 7 years, when the study was interrupted. The data arising from that study were given to the large public, not as a treatment on an aging population but as for a specific treatment for the menopause symptoms therapy, without any consideration on the fact that in these women menopause can happen one month or more than 20 years before the beginning of treatment.

The time since the Menopause was so different that when the same authors in further studies examined the impact according to the time from menopause (less than 10 years, between 10 and 20 years and more than 20 years) , the group of patients closer to menopause in fact also in the WHI study, showed a positive effect of hormone therapy even in the risk that they were claiming on for hormonal therapy.

Millions of women all around the world interrupted their treatment, the major companies producing Hormone Replacement Therapy made bankrumpt or were sold to other companies, researchers, employees and workers were dismissed, and a misogynist crusade against hormone use in women started in all Countries.

The general ignorance of hormone effects, the lack of culture and mainly the fear associated to the ignorance, were the major actors in our scenario.

Since the interruption of hormone therapy and the denial to prescribe this treatments after menopause, the number of osteoporotic fractures, myocardial infarct, Alzheimer diseases, depression and all other diseases linked to the women lack of sex steroids, increased suddenly all over the world.

In Europe we activated new studies and we exploited the Women’s Health National registries data, such as in Denmark and Finland, which allowed us to publish studies, demonstrating that treating symptomatic women since the moment of Menopause with Estradiol (the European Estrogen), and different gestagens (with the exclusion of MPA) or micronized progeterone, the impact on cardiovascular system was clearly protective and same for brain and all other body organs and tissues.

Also for the breast, the use of hormones selected for women by nature, was free of additional risk.

Human life start surrounded and protected by sex steroids and these substances continues their positive impact on cell biology during all life.

The Americans were obliged to reanalyse their results, and some group started providing new date showing that a critical factor is to start the hormone therapy as earlier as possible, even before menopause and others have also agreed that the quality of progestogens can make the difference mainly for the breast effects of these treatments.

Now, a new sunrise is facing us: hormone therapy with estradiol, manly for transdermal route of administration, and with micronized progesterone represents for the greatest majority of women the proper way to correct the symptoms of the menopause and to protect all steroid sensitive organs from the impact of the hormone withdrawal of the menopause.

The length of treatment have to be individualized according to the personal needs and general timing is normally over 10 to 15 years (Nat Rev Endocrinol. 2013 Jan;9(1):5-6 ) .

In addition to the general therapy, local treatments can be associated to enhance the effects on genital tract according to the needs, to improve vulvo vaginal atrophy and to protect women sexual life.

And this is not the last word… from the most recent studies, other substances appears to increase the women protection and to reduce their natural risks… Estetrol, the Estrogen protecting mother and fetus during pregnancy, clearly shows its possibilities and advantages in the use in women therapies…. now in contraception and in the very close future in Post-Menopause therapy.

The G-D smile appears again between… the courtains.


1. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial, J. Am. Med. Assoc.; 288:321–333, 2002. 

2. Genazzani AR, Gambacciani M., A personal initiative for women’s health: to challenge the Women’s Health Initiative, Gynecol. Endocrinol.; 16:255–257, 2002. 

3. Nat. Rev. Endocrinol. 2013 Jan;9(1):5-6. doi: 10.1038/nrendo.2012.228. Epub 2012 Nov 27. Pharmacotherapy: Benefits of menopausal hormone therapy--timing is key, Genazzani AR, Simoncini T.