Soy isoflavones, lactobacilli, calcium and vitamin D3. Observational study in menopause. Arcoraci V. 1, Caputi A.P.1, Benvenuti C.2, Estronet Study group* 1Clinical and Experimental Dept. of Medicine and Pharmacology, University of ; 2Medical Dept, Rottapharm, , Rationale of the study Methods Recent scientific acquisitions and regional differences in On an internet based computerised procedure (www.estronet.net), pharmacological approach have remodelled the prescription attitude in each gynaecologist observed up to 10 consecutive menopause women. menopause. The project was designed to draw an updated profile on History, life-style, past and actual treatments, HRT refusal/withdrawal, the actual trend of Italian Gynaecologists in menopause management current pharmacological therapy, symptoms evaluation, visits/exams in in clinical practice and to detect the clinical activity of a new the 3 months preceding the visit, were recorded. phytoestrogen, in which isoflavones are combined to lactobacilli, Confidential access, protected by individual login and password allowed data input and data consultation by 181 gynaecologists. The vitamin D3 and calcium, in clinical practice. characteristics of the not treated (NT), on hormone replacement Results therapy (HRT) and using phytoestrogens women were compared. The study was carried out between May 2003 and June 2004 on 1384 menopause women (spontaneous 86.6% surgical 13.4%) Fig. 1 Menopause treatment Fig. 2 HRT refusal/withdrawal reasons 50.0 (Fig. 1and 2). The most used phytoestrogen in the study 50 % 43.9 % 43.9 ent Es Ph NT es in 693 women Age (yrs) 53.3 54.1 55.5 tm 40 33.5 as 40.0 BMI (kg/m2) 24.1 24.8 24.6 c 33.6

(87.1%) contains genistine and daidzine (30+30 mg) + f 30 SBP (mmHg)126.5 127.7 127.8 o

trea 23.6

f DBP (mmHg) 77.9 78.3 78.8 30.0 y o 20 HR (beat/min)76.2 75.0 76.7

lactobacilli, Ca and vit D3 [Estromineral (EM)] and was nc 19.8 ce 20.0 15.9 10 ue administered to 392 women for a mean duration of 112.9 days. n=327 n=464 n=607 Choi 0 10.0 Freq 4.5 oestrogens phyto no treatment 3.6 3.6 2.7 2.3 estrogens 1.4 In EM, the conversion of isoflavones in active aglyconic forms is spray 0.0 e d gel ar al ng es or of e ear s ch ed ct ifie e s f f logi o c 6% c m r n o rm e 12% in combination 1.1% n o o refu eedi t ada fo p e t gai bl in ily d s guaranteed by Lattobacillus sporogenes (L.s.) (Fig.4). s p t m pa He t n m Tum h th o Ab y g y nal er no fam n s i h / e Rh agi d by se W v Ot e os ar p sed Diet was more adopted by women on EM (30.4) and HRT oral opau n pro e regul advi Ir r 18% transdermal m ve Un (28.7%) than by NT (22.2%); smoking ranged between 15.3% in 64% ne EM and 17.3% in NT group; coffee/tea and milk derivatives Fig. 3 Education Fig. 4 Conversion of isoflavones % in active forms by L.s. consumptions ranged both between 81% in NT and 88% in HRT 40.0 100.0 36.6 NT % % formed daidzeine s 33.9

e 35.0 98.2 30.9 HRT/ERT s group; physical activity between 28.1% in EM group and 33.6% phytoestrogenes n 80.0 % formed genisteine 87.5 a 29.0 28.9 30.0 27.7 o c c y f 22.0

o 21.5 in HRT regimen. Women treated (HRT or EM) underwent more 25.0 20.9 60.0 y 20.0 19.2 agl nc 15.2 14.2 ed 40.0 m exams both before and during the treatment than NT women ue 15.0 10.0 20.0 ** Freq ** (Fig. 5). % for 5.0 2.4 2.0 0.0 0.0 Primary Secondary High school University soy isoflavones soy isoflavones + L.s. Fig. 5 Exams carried out school school before treatment within 3 months before the visit ** p< 0.01 vs Isoflavones + L.s. 100.0 90.5 s 90.1 84.4 87.8 100.0 e % 82.4 80.4 % NT HRT/ERT EM s 73.0 75.2 a 80.0 67.1 69.4 65.9 80.0 c 61.8 f 59.2 58.1 o 53.5 60.0 48.9 55.0 54.4 At start, the most present symptoms on EM treatment were

y 60.0 53.6 49.5 45.2 43.4 48.0 48.3 41.7 39.0 41.8 nc 40.0 43.6 43.4 41.2 37.8 40.0 33.6 39.4 34.6 30.3 flushing and nocturnal sweating (Fig. 8). The rate of EM ue 29.2 20.0 11.6 20.0 9.9 10.2 Freq responders was independent from the severity at start (Fig. 9). 0.0 gynaecological PAP test pelvic mammo Bone Mineral 0.0 lipid hepatic coagulation oestradiol PAP test pelvic mammo BMD visit echography graphy Density profile function screening echography graphy The clinical response to EM increased in relation with treatment duration (fig. 10) and was superior compared to the alternative Fig. 6 Clinical concomitant Fig. 7 Concomitant therapies 25.0 conditions 25.0 phytoestrogen group, as flushing and nocturnal sweating were % % 20.6 21.620.9 20.4 21.2 NT HRT/ERT EM s concerned (fig. 11). e 19.3 18.0 20.0 19.1 es 20.0 s 17.7 17.7 17.9 16.8 a 16.5 as

c 14.8 c 15.8 f f 13.3 o 15.0 15.0 13.3 o y 11.3 y 10.4 10.4 11.0 Fig. 8 Severity of symptoms Fig. 9 Clinical activity of EM related nc nc 8.6 10.0 10.0 6.4 7.4 at EM treatment start to symptom severity at start ue

ue 6.7 5.9 5.8 5.9 5.8 3.1 3.1 4.9 EM: isoflavones +LB+ Ca +vit.D mild moderate severe 3.4 3 s Freq 5.0 5.0 2.6 1.8 2.5 Freq 2.4 2.5 2.6 3.0 e 1.5 0.6 60.0% s 100.0 absent moderate a % 88.2 88.0

c 85.5 s 51.4 83.1 85.8

0.0 e mild severe arthrosis osteo hyper coronary diabetes benign breast K. 0.0 bis calcium anti anti anxyolitics anti thyroid 78.5 s 50.0 80.0 71.4 porosis tension hd/ami mammary disease phosphonates + vit.D inflammatory hypertensives depressants hormone a 42.1 68.2 64.7 c 37.4 f 40.0 59.3 60.0 o

33.2 33.2 proved 32.2 33.0 60.0 48.2 y 28.8 27.4 30.0 im f nc

In presence of concomitant pathological conditions, the rate of o 40.0 ue 20.0 16.9 16.7 y 12.2 13.7 13.6 EM users was higher than HRT users and similar to non treated nc 20.0 Freq 10.0 6.4 1.7 ue 0.0 0.0

incidence (Fig. 6). When breast cancer was involved, the Freq flushing nocturnal palpitations vaginal flushing nocturnal palpitations vaginal treatment choice felt almost exclusively on EM or NT. Data on sweating dryness sweating dryness concomitant therapies show the compatibility of EM with different pharmacological classes (Fig. 7). Fig. 10 Clinical activity of EM Fig. 11 Comparison between EM Conclusions related to duration of treatment and other phytoestrogens % 10100.0.00 flushing nocturnal vaginal

This observational study confirmed the reasons for 10s 0.0 sweating dryness e 2 s 95.95.33 95.95.77 95.95.22 96.96.22 100.0 p= 0.035 p= 0.07 NS χ a % 2x3 c 90.90.00 86.3 refusal/withdrawal of HRT. 86.86.88 s 82.7 83.83.11 flushing e 80.0 84.84.66 nocturnal sweating s 72.1 80.0 a 70.5 palpitations Women treated (HRT or phytoestrogens) appear more c f proved vaginal dryness

o 60.0 72.72.11 70.70.00 55.1 55.9 y im 68.68.22 f 43.2

controlled both before and during the treatment. o 63.63.66 nc 38.2

y 60.0 56.56.33 40.0 56.56.00 57.57.11 ue 27.9 27.3 nc 56.56.33 In presence of concomitant clinical conditions, the natural 52.52.22 17.0 ue

Freq 20.0 13.1 45.45.33 5.9 42.42.99 2.3 1.8 approach with phytoestrogens are preferred. Freq 40.0 0.6 0.0 0.3 0.0 024681012 EM Other EM Other EM Other Phytoestrogens plus lactobacilli and mineral supplement show a Months of treatment phytoes phytoes phytoes satisfactory clinical activity, correlated to duration of treatment unchanged improved worsened Acknowledgements. We thank Ibis Informatica for the website realisation and the statistical and greater to the one of other phytoestrogens. analysis and Angela Ponzoni for the secretarial assistance to the project. *Es*Esttroneronett sstudytudy groupgroup Agnello A., Padova; Agostinelli D., ; Albertin E., Ponte S. Nicolò (PD); Alio L., ; Amato M. Teresa, Caltagirone (CT); Anelli R., Cusano Milanino (MI); Arienzo M., Napoli; Baj G., ; Baldaccini E., Alatri (FR); Baldini M., Loc. Quarto (PC); Barbadori M.A., ; Barbaro M. Luisa, Messina; Bartolini T., Lucca; Battistella G., Teramo; Belsanti A., Andria; Benanti R., Palermo; Benatti G., Soliera (MO); Bergamaschi D., Mestre (VE); Bertarini W.; Bertocchi L., ; Bianca M., Avola (SR); Biancheri D., Bordighera (IM); Bocconi L., Milano; Bolelli E., Bologna; Bordin G., ; Bori S., Perugina; Bray F., Melegnano (MI); Brun A, Pozzuoli; Cagnacci A., ; Calvisi L., ; Campanelli T., Spoleto (PG); Carmina A., Palermo; Carrubba M.,Caltanissetta; Cascio A., Casier (TV); Cascio N., ; Caselli C., ; Cataldi U., ; Cavanna L., Torino; Cazzavacca R., ; Ceccarelli P., Lucca; Cerini M.R., Novara; Cerreoni A., Cesena; Chionna R., Palazzo P. (CR); Chirico C., ; Ciccone C., Avellino; Cirillo S., ; Colonnelli M., Perugina; Conti C., Fano (PU); Coppola C., Torino; Costabile L., Caserta; Cotardo R., Torino; Cuciniello A., Angri (SA); Cusmai R., Brescia; De Angelis P., Popoli; De Giorgi A., S. Cesario (LE); De Matthaeis L., Mesagne (BR); De Troia L., Roma; Della Peruta S., Arona (NO); Di Natale R., Palermo; Dimaggio A.,; Ercolano S., Castellammare di Stabia (NA); Favi O., ; Ferruccio C., Mesagne (BR); Filippa N.,Vigevano ; Fiorillo F., Napoli; Fontanesi V., Albinea (RE); Franchi F., Siena; Frattini G., Fano (PU); Gaias A., ; Galantino P., Bari; Gallo M., Torino; Garofalo M., Cosenza; Gherardini D., Portice (MO); Giardina S., ; Giorgino L.F., Padova (PD); Gobbi F., Rivoli (TO); Gravina G., S. Severo; Graziano R., Palermo; Guastaferro L., Modena; Guidoni G. C., Siena; Izzo S., Benevento; La Moglia A., Napoli; La Placa A., ; Laneve M., ; Lentini G., Palermo; Leonardi M., Brescia; Levanti S., Pisa; Licata A., Enna; Loiudice L., Bari; Lucianetti M., ; Macri G., Locri (RC); Maestrini G., Firenze; Maggiorelli M., Pratolino (FI); Mancini A.C., Modena; Mancuso M., ; Marchetto G., Treviso; Marcozzi S., Milano; Mariatti M., Orbassano; Martinelli M., Roma; Mastrorosa F., Brindisi; Matteucci G.M., ; Mazza R., ; Menciotti M., San Gemini (TR); Milia R., Monza (MI); Minotti A., Carate Brianza (MI); Misitano G., Vigevano ; Mocci C., Roma; Mora S., Chieri (TO); Moroni S., Milano; Moscatelli C., Rovereto (TN); Mucci M., Ortona (CH); Muciaccia A., Brescia; Nicolucci S., Lanciano (CH); Nirta A., Cirié (TO); Nitti M.G., Napoli; Nocera F., ; Nozza M., Verdello (BG); Ollago A., Mantova; Ortu G., Padova; Pacca N., ; Paganotti C., Brescia; Paltrinieri F., Forlì (FC); Pandolfo M. C., Palermo; Parrini A., San Vincenzo (LI); Patton R., ; Pellegrini F., ; Pellegrini S., Jesi (AN); Perini R., Sesto Fiorentino (FI); Pilia I., ; Poli M., Milano; Polo C., Rovigo; Pozzuoli P. L., Caserta ; Pretolani G., ; Procaccioli P., Ascoli Picero; Pupo C.D., Soverato (CZ); Quagliarini V., Senigallia (AN); Repetto P. ; Ricci L.., Padova; Ricciardo G., Vigevano; Risalvato I., Cagliari; Roccato M.,; Rossi M., Bollate (MI); Ruggeri C., Brescia; Saia R., Abano (PD); Salvestroni C., Cristina; Sammartino A., Napoli; Sangiorgi B., Vasto (CH); Sansone M., Napoli; Santeufemia S., Cagliari; Santilli C., Pescara; Santomauro S., Palermo; Scaglione G., Palermo; Scopelliti A., Foggia; Scuderi G., Erba (CO); Senatore G.,Eboli (SA); Serafini T., Bologna; Sironi L., Sesto S. Giovanni (MI); Solesin M., Noventa di Piave (VE); Sorbilli E., Vercelli; Sordi G., Villafranca (VR); SpinaciL., Milano; Spolti N., Melegnano (MI); Stella D., Ravenna; Stillo A., Milano; Tafuri A., Roma; Tamburrino A., Secondigliano (NA); Taroni B., Bologna; Tomasillo G., Napoli; Tomei T., Scandicci (FI); Torciano L., (BA); Turco S., Milano; Ullo F., Valdina (ME); Vanzetto M.C., Roma; Vasoin F., Padova; Vero I.G., Catanzaro; Vescio F., Lamezia Terme (CZ); Volonterio A., Cusano Milanino (MI); Volpini G., Roma; Votano S., Roma; Waldthaler L.,; Zanini P., Cerea (VR). 12th World Congress on Human Reproduction, 10-13 March 2005, , Italy