Effect of the ethinylestradiol/norelgestromin contraceptive patch on body composition. Results of bioelectrical impedance analysis in a population of Italian women

<p>Abstract</p> <p>Background</p> <p>As weight gain is one of the most frequently cited reasons for not using and for discontinuing hormonal contraceptives, in an open-label, single-arm, multicentre clinical study we evaluated the effect of the ethinylestradiol/norelgestromin contraceptive patch (EVRA, Janssen-Cilag International, Belgium) on body composition using bioelectrical impedance analysis (BIA).</p> <p>Methods</p> <p>Body weight and impedance vector components (resistance (R) and reactance (Xc), at 50 kHz frequency, Akern-RJL Systems analyzer) were recorded before entry, after 1, 3 and 6 months in 182 Italian healthy women aged 29 yr (18 to 45), and with BMI 21.8 kg/m²(16 to 31). Total body water (TBW) was estimated with a BIA regression equation. Vector BIA was performed with the RXc mean graph method and the Hotelling's T²test for paired and unpaired data.</p> <p>Results</p> <p>After 6 months body weight increased by 0.64 kg (1.1%) and TBW increased by 0.51 L (1.7%). The pattern of impedance vector displacement indicated a small increase in soft tissue hydration (interstitial gel fluid). Body composition changes did not significantly differ among groups of previous contraceptive methods. Arterial blood pressure did not significantly change over time.</p> <p>Conclusion</p> <p>After 6 months of treatment with the ethinylestradiol/norelgestromin contraceptive patch we found a minimal, clinically not relevant, increase in body weight less than 1 kg that could be attributed to an adaptive interstitial gel hydration. This fluctuation is physiological as confirmed by the lack of any effect on blood pressure. This could be useful in increasing women's choice, acceptability and compliance of the ethinylestradiol/norelgestromin contraceptive patch.</p

Direct Vascular Effects of Estrogens and SERMs

The aim of this review is to provide an update on the latest advancements in the field of the action of estrogens on the cardiovascular system, and particularly on the molecular mechanisms of the direct effects of these hormones and of some of the new synthetic selective estrogen receptor modulators on the vascular wall

Timing is everything

Background Limited information is available on the effects of progestins on breast cancer progression and metastasis. Cell migration and invasion are central for these processes, and require dynamic cytoskeletal and cell membrane rearrangements for cell motility to be enacted. Methods We investigated the effects of progesterone (P), medroxyprogesterone acetate (MPA), drospirenone (DRSP) and nestorone (NES) alone or with 17β-estradiol (E2) on T47-D breast cancer cell migration and invasion and we linked some of these actions to the regulation of the actin-regulatory protein, moesin and to cytoskeletal remodeling. Results Breast cancer cell horizontal migration and invasion of three-dimensional matrices are enhanced by all the progestins, but differences are found in terms of potency, with MPA being the most effective and DRSP being the least. This is related to the differential ability of the progestins to activate the actin-binding protein moesin, leading to distinct effects on actin cytoskeleton remodeling and on the formation of cell membrane structures that mediate cell movement. E2 also induces actin remodeling through moesin activation. However, the addition of some progestins partially offsets the action of estradiol on cell migration and invasion of breast cancer cells. Conclusion These results imply that P, MPA, DRSP and NES alone or in combination with E2 enhance the ability of breast cancer cells to move in the surrounding environment. However, these progestins show different potencies and to some extent use distinct intracellular intermediates to drive moesin activation and actin remodeling. These findings support the concept that each progestin acts differently on breast cancer cells, which may have relevant clinical implications

Tibolone inhibits ELAM expression

Tibolone is a synthetic steroid with mixed estrogenic and progestogenic/androgenic activity used for post-menopausal hormone replacement therapy. Since its cardiovascular effects are still not clear, and no data have been published on possible direct actions on the vessel wall, we studied the effects of tibolone and its metabolites on lipopolysaccharide (LPS)-induced expression of leukocyte adhesion molecules on human endothelial cells. Tibolone and its two estrogenic 3alpha-OH and 3beta-OH metabolites, but not the progestogenic/androgenic Delta(4)-isomer, concentration-dependently decreased LPS-induced vascular cell adhesion molecule-1 protein expression. This effect was estrogen receptor dependent, since it was completely blocked by the pure estrogen receptor antagonist ICI 182780. Furthermore, only tibolone, the 3alpha-OH and the 3beta-OH metabolites decreased endothelial expression of E-selectin, while none of the compounds changed the levels of intercellular adhesion molecule-1. These findings were associated with parallel changes in mRNA levels for the three adhesion molecules. Our data show that tibolone and its estrogenic metabolites exert direct actions on the vascular wall, decreasing the expression of endothelial-leukocyte adhesion molecules, thus producing potentially important direct anti-atherogenic effects

Dehydroepiandrosterone, the Endothelium, and Cardiovascular Protection

Dehydroepiandrosterone (DHEA) sulfate (DHEAS) is the most abundant circulating steroid hormone in humans (1). Although there are wide variations, the plasma concentrations of DHEA and DHEAS progressively decline with age (2, 3, 4), suggesting that they may be implicated in the aging process, and perhaps in cardiovascular aging, on which has been built a case for DHEA supplementation in aging individuals. Over the past 10 yr, preparations of DHEA have been available over the counter and on the internet and have been sold as the “fountain of youth.” This has raised concerns about the possible effects of such uncontrolled and widespread hormonal self-administration and the lack of quality control in this increasingly rewarding business. Although DHEA replacement may seem an attractive theoretical concept, there are very few definitive reports on the biological functions of this steroid, and it is still the case that its regulation is unclear and its mechanisms of action largely yet to be established. In this issue of Endocrinology, Liu et al. (5) make an important contribution to this area, on the molecular actions of DHEA. Based on a variety of approaches, Liu et al. elegantly show that DHEA acts as a survival factor for vascular endothelial cells. This observation is a point of departure for some of the reported beneficial actions of DHEA on the vascular system and may provide a rationale for the epidemiological linkage of DHEA and cardiovascular disease. Several epidemiological studies have shown an inverse correlation between DHEA/DHEAS plasma concentrations and mortality, particularly mortality due to cardiovascular disease. The Rancho Bernardo study was the first to correlate DHEAS levels with cardiovascular risk in males over 50 yr of age (6). Subsequently, a number of studies have extended this observation to young men (7) as well as to premenopausal (8) and postmenopausal women (9). Low DHEAS levels have been also associated with cardiovascular events (10), with the extent of angiographic coronary stenosis (11), as well as with allograft vasculopathy (12), suggesting a role for DHEAS in delaying coronary disease. Not all the studies are concordant in showing a cardioprotective action of DHEA. For example, the later reanalysis of the Rancho Bernardo cohort showed a much weaker correlation between the peripheral levels of the steroid and coronary heart disease (13). However, relatively recent evidence from the prospective PAQUID study has renewed interest in this issue, again showing higher mortality in male patients correlated with lower DHEAS concentrations (14, 15). These clinical findings are supported by animal studies that indicate a protective role of DHEA against atherosclerotic disease in primates (16) and rabbits (17, 18), although the identification of the mechanisms involved is still work in progress. The great conundrum in this area is the lack of a clear mechanism of action of DHEA. It is known that this steroid serves as a precursor for estrogens and androgens, and many believe that DHEA is merely an inactive precursor pool for the formation of bioactive steroid hormones. To this extent, oral supplementation of DHEA in postmenopausal women results in the formation of significant amounts of 17β-estradiol and estrone, accompanied by increases of androstenedione, testosterone, and dihydrotestosterone (19). This, plus the evidence that DHEA can also be converted into estrogens and other androgens within cells (20), supports the view that many actions of this steroid are indirect and mediated via estrogen and/or androgen receptors. This may also be true for blood vessels, as shown by a report indicating that the reduction of atherosclerotic lesions by DHEA in rabbits is in part mediated by conversion to estrogens (21). There is, however, increasing evidence for DHEA acting in its own right through a dedicated, although as yet unidentified, receptor. The existence of such a receptor for DHEA has been particularly investigated in vascular cells, where DHEA binds with high affinity to the endothelial cell membrane, and is not displaced by structurally related steroids (22). Binding of DHEA to the cell membrane is coupled to recruitment of G proteins such as Gαi2 and Gαi3 that mediate the rapid activation of intracellular signaling cascades (22) (Fig. 1⇓). Our own data support these results of rapid recruitment of G proteins at the cell membrane and later recruitment of ERK 1/2 MAPK when DHEA is added to human endothelial cells in vitro (23) (Fig. 1⇓). These effects are not prevented by the blockade of androgen or estrogen receptors, and DHEA signals via the endothelial nitric oxide synthase, which is rapidly recruited to increase synthesis of nitric oxide, a powerful vasodilator and antiinflammatory agent (23) (Fig. 1⇓). The induction of nitric oxide synthesis by DHEA is thus highly relevant for vascular function and may provide a mechanistic explanation for the antiatherogenic effects of this steroid in animals (21) and in humans, as well as for its antiinflammatory (12) effects. The present report by Liu et al. further extends the biological reach of this steroid and shows that part of its alleged antiaging actions in vessels may reflect a reduction of programmed cell death in the endothelium. This action of DHEA requires recruitment of a cell membrane G protein of the Gαi family and is independent of the conversion of DHEA to estrogens and the estrogen receptor. The other remarkable observation in the paper by Liu et al. is that DHEA triggers a rapid recruitment of the phosphatidylinositol 3 OH kinase/Akt pathway, which mediates the antiapoptosis action of DHEA (Fig. 1⇓). Recruitment of this pathway is a common feature of different steroid receptors (24), including the estrogen receptor α (24, 26), the progesterone receptor (27), and the glucocorticoid receptor (28). This suggests that this particular action might be a basic and necessary function of nuclear receptors that has been conserved throughout evolution. If this is true, it might also suggest that the yet-uncharacterized receptor for DHEA might belong to this large family of receptors, although evidence for additional family members is lacking. Alternatively, it may be truly a membrane-located seven-transmembrane G protein-coupled receptor, which constitutes a much larger receptor family. In conclusion, although there is still debate on DHEA, there is already compelling evidence that this steroid is not just an inactive side product of the adrenals, but rather a hormone in its own right, and that it modulates a series of processes in the body. Only future research will tell whether this steroid is or is not implicated in the aging process or in vascular degeneration. Even in the evidence-based third millennium, the dream of a natural fountain of youth is an enticing one for which answers are likely to come over the next decade

Documento di Consenso, Menopausa e Terapia Ormonale Sostitutiva Conferenza Nazionale di Villa Tuscolana, Frascati (Rome), May 8-9, 2007

La pubblicazione dello studio randomizzato WHI nel luglio 2002 ha fatto vacillare molte certezze sulla terapia ormonale sostitutiva (HRT, Hormone Replacement Therapy) in menopausa. Precedentemente, la maggior parte degli studi preclinici ed osservazionali avevano dimostrato che la HRT determina una riduzione del rischio di malattia coronarica (CHD, Coronary Heart Disease), potendo altresì ridurre il rischio o posporre l’insorgenza di deficit cognitivi e demenza senile. Al contrario, i risultati del WHI non hanno confermato questi dati. La diversità tra questi risultati è chiaramente dovuta alla selezione delle donne ed al momento di inizio della HRT in funzione sia della età anagrafica che degli anni trascorsi dalla menopausa. Negli studi osservazionali, gli ormoni erano stati prescritti a donne durante la transizione menopausale, la maggior parte delle quali era sintomatica, e di età generalmente inferiore ai 55 anni al momento dell’inizio della terapia. Al contrario nel WHI, la HRT è stata iniziata oltre i 55 anni in oltre l’ 89% delle donne, cominciando ex novo dopo molto tempo dall’ultima mestruazione e in larghissima parte in pazienti che non avevano sintomi menopausali. Negli studi osservazionali è stata rispettata la “finestra delle opportunità” (window of opportunity) entro la quale una precoce sostituzione ormonale, in donne più giovani e sintomatiche, è capace di proteggere dagli effetti endocrino-metabolici e clinici della carenza estrogenica. Questo è in accordo con la fisiopatologia dei processi degenerativi dell’invecchiamento, quali l’aterosclerosi e la © Copyright 2007, CIC Edizioni Internazionali, Roma neurodegenerazione che richiedono parecchi anni per Menopausa e Terapia Ormonale Sostitutiva Conferenza Nazionale di Villa Tuscolana (Frascati, Roma 8-9 Maggio 2007) A.R. GENAZZANI, M. GAMBACCIANI, T. SIMONCINI Ginecologia, Pisa Giorn. It. Ost. Gin. Vol. XXIX - n. 6/7 Giugno-Luglio 2007 213 documento di consenso svilupparsi. Nel WHI sono state invece trattate donne anziane in cui la tardiva somministrazione di ormoni non ha potuto prevenire alterazioni degenerative ormai presenti a livello cardiovascolare. Un precoce inizio della HRT, sia in termini di età che di anni dalla menopausa, può rappresentare un fattore determinante sia per determinare alcuni effetti positivi (riduzione del rischio cardiovascolare e del rischio di Alzheimer) che per limitare eventi avversi (trombosi venosa, ictus). Inoltre lo studio WHI, per le caratteristiche delle pazienti (età, comorbidità, peso corporeo, uso di farmaci cardiovascolari), non può essere considerato in realtà uno studio di prevenzione primaria condotto in donne sane in postmenopausa. Sebbene fosse stato disegnato (e successivamente presentato) come uno studio randomizzato e controllato con placebo, l’alta incidenza di “drop-out” e di sintomi rivelatori (sanguinamenti vaginali, tensione mammaria) rendono difficile considerarlo un credibile studio in doppio cieco. Inoltre, le pazienti incluse nel WHI non rappresentano la popolazione di donne sane in età perimenopausale o di recente in postmenopausa che abitualmente richiedono una consulenza per il trattamento della sintomatologia climaterica. Recentemente, Rossouw et al. (2007) hanno rivalutato i dati dello studio WHI sulla base dell’età delle pazienti e del tempo trascorso dalla menopausa al momento dell’arruolamento. Pur in assenza di significatività statistica, questa nuova analisi dimostra che l’aumento del rischio cardiovascolare riportato nei primi studi pubblicati è da attribuirsi, essenzialmente, alle pazienti che cominciano il trattamento in età più avanzata e a maggiore distanza dalla menopausa. Al contrario nelle donne più giovani (50-59 anni) trattate con HRT l’incidenza delle malattie cardiovascolari e la mortalità diminuiscono. La cultura e la percezione dell’importanza della HRT sono state comunque profondamente modificate dalle interpretazioni non corrette del WHI. In tutto il mondo la pubblicazione del WHI e dello studio osservazionale inglese noto come “The Million Women Study”, in cui è stata valutata la frequenza di tumore mammario in donne che partecipavano ad un programma di screening mammografico nel Regno Unito e correlata all’uso di HRT, ha portato ad una riduzione dell’utilizzo di HRT fino al 30-40%, che ha interessato soprattutto le donne meno informate. A dimostrazione di ciò, le donne medico e le mogli di medici sono la categoria in cui è tuttora maggiore l’utilizzo di HRT. Le donne medico italiane rimangono le maggiori utilizzatrici di HRT, e solo l’8% di esse ha interrotto la HRT dopo la pubblicazione del WHI. Nella maggior parte dei casi, il calo dell’utilizzo dell’HRT ha interessato in maniera non specifica tutte le preparazioni commerciali disponibili e non solo quella utilizzata nel WHI (estrogeni coniugati equini, 0.625 mg/die, in associazione a medrossiprogesterone acetato, 2.5 mg/die). Le nuove prescrizioni sono calate più delle interruzioni di terapia. Una quota significativa delle donne che hanno interrotto la HRT hanno successivamente ripreso un trattamento ormonale per ricomparsa dei sintomi. Tra le nuove terapie sono aumentate le associazioni a basso dosaggio