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Editorial

The quality of life and the prevention became major objectives of medicine. In 2030 more than 45 million women will be postmenopausal (Hill K, 1996). The hormonal replacement therapy (HRT) of the menopause after having been the standard gold necessary to maintain the wellbeing of the woman up to 50 years old, had become the treatment to be avoided after the publication of the first disastrous results of the prospective studies of Women Health Initiative randomized Trial (WHI), of Heart and Estrogen/Progestin Replacement Study (HERS) and of the Million Women Study (MWS). Since, re-analyzes of the WHI and new prospective studies brought to reconsider the use of the hormones. Amos Pines, past President of the International Society of Menopause (IMS), summarizes the current recommendations elaborate by the IMS.  He describes perfectly the difficulties which have, currently, large scientific Societies to define precise recommendations on the treatment of the climacteric symptoms of the menopause taking into account the difficult evaluation of the balance benefit/risk which appears to vary much from one individual to another.

Among the climacteric symptoms, the urogenital atrophy is often under-estimated in spite of it can become awkward. The article of M.P. Brincat and J.Calleja-Agius which points out their work recently published (Climacteric, 2009) described very well the biological mechanisms implied in this atrophy. They underline the beneficial role of estrogens contrasting with their deleterious role on the breast cancer. The compromise with weak estrogens as the estriol is discussed as well as the possible use of SERM.

Cardiovascular pathologies remain a major cause of death at the old woman. U. Gaspard submits an excellent report on the Workshop "Ageing, Menopause, Cardiovascular disease and HRT" organized in Pisa. It confirms the important role of the steroid hormones in the development of the vascular endothelium and its reconstitution after a vascular traumatism. During theWoskshop, authors also insisted on the role of estrogens in the fragmentation of the atheroma and the existence of a beneficial effect of the HRT if it is taken precociously whereas it is deleterious when it is begun tardily.

The risk of breast cancer remains one of the major counter-indications of the HRT although the use of natural hormones limits to a significant degree this risk:

- the estrogens alone, with low dose, have non significant effects on the incidence of the breast cancers up to 8 years of HRT (Fournier A, 2008; Lyytinen H et al., 2009) but have a significant effect on the climacteric symptoms and the osteoporosis. A recent work comparing the WHI and an observational study based on 17437 women included starting from 40 clinical centers the USA, do not show a difference in risk of breast cancer among women precociously beginning the HRT after the menopause or after a delay which can go beyond 15 years (p=0.82) (Prentice RL and collar, 2008a). This re-analyzes comprised data up to 5 years of treatment;

- under estro-progestins, the relative risk of breast cancer, evaluated according to studies' at 1.25-2, depends on the progestin one. Study E3N (Fournier A, 2008) and a recent Norwegian study (Lyytinen H et al., 2009) shows that the natural progesterone and the didrogesterone associated the 17b-Estradiol do not increase to a significant degree the risk of breast cancer whereas the progestins of synthesis increase this risk. This observation raises two questions. That of the deleterious role of the progestins of synthesis which the mechanism remains discussed. The other question is that of the apparent harmlessness of natural progesterone. One of the probable explanations is that the progesterone, very quickly metabolized by the digestive tract, arrives at very weak concentrations in the target tissues and its quantity might be negligible in the breast;

- the interval of time betweens the installation of the menopause and the beginning of the HRT. A more recent work comparing an observational study of 16.608 women recruited in 40 centers the USA and the WHI shows that the risk of breast cancer is higher among women beginning the HRT (0.625 Mg of the EEC with 2.5mg of MPA) very early in the menopause compared to the women begin tardily and this in a all the more significant way as the HRT is started tardily (subgroups of <5 years, 5-15 years and >15 years of time after the installation of the menopause) (Prentice RL, 2008b). The women who take it precociously and in a prolonged way are more at the risk (more than 5 years). The study of biomarkers (RE, P53...) and of many clinical observations show that there is indeed an opposite correlation between the age and tumoral aggressiveness suggesting that the biology of the breast cancers is dependant on the age (Benz DC, 2008). On the histological level, the studies are rather consensual and finds a higher risk of lobular cancer than of ductal cancer (ex: Lyytinen H, 2009; Baker A et al., 2008).  There is also an involution of the lobules of the  mammary gland increasing with the age (Milanese TR and collar, 2006) and the incidence of the breast cancers is inversely proportional to the involution of the breast. It is thus possible that by tardily beginning the HRT, the senile involution of the mammary lobules and the biology of the  breast cells early decrease the incidence of the breast cancers compared to the women taking a HRT early in the menopause.

The evaluation of the effective amount of estrogens showed that the weak ones even of very low dose of estrogen were sufficient to treat the climacteric symptoms of the menopause (Prestwood km and collar, 2003, Peeyananjarassri K and Baker R. 2005, Palacios S, 2008). Studies convergent to show that these low dose of estrogen also makes it possible to decrease the osteoporosis and to have a protective cardiovascular effect (Peeyananjarassri K and Baker R. 2005). This effect would be stronger if the rate of endogenous free estrogen is low (Huang AJ et al. 2007).

To conclude, the clinician is currently confronted precociously to propose a HRT, before the alteration of the vascular endothelium, in the event of cardiovascular risk or if not of advising a late use in order to limit the risk of breast cancer. Consequently, according to the personal and family history of the patient and of its age, the balance risks/benefit of the use of the HRT varies. The interest to use quantifiable indices appears increasingly obvious if one wants to establish homogeneous recommendations. Remain to work out them!

Benz CC. 2008 Crit Rev Oncol Hematol;66:65-74.

Calleja-Agius J, Brincat MP. 2009 Climacteric Apr 22: 1-7

Fournier A et al. 2008 J Clin Oncol.;26:1260-1268.

Hill K. 1996 Maturitas ; 23 : 113-127.

Huang AG et al. 2007 Bone Miner Res. ; 22 : 1791-1797.

Ismail PM et al 2003 Steroids;68: 779-787.

Lyytinen H et al 2009 Obstet Gynecol; 113:65-73.

Prentice RL et al. 2008a, Am J Epidemiol ; 167 :1407-1415.

Prentice RL et al. 2008,b Am J Epidemiol ; 167 :1207-1216.

Milanese TR et al. 2006 J Natl Cancer Inst. ; 98 :1600-1607.

Palacios S. 2008 BMC Women's Health ; 8 : 22-26.

Peeyananjarassri K et Baker R. 2005 Climacteric; 8: 13-23.

Prestwood KM et al. 2003 JAMA;290: 1042-1048.