Menopausal Management Options: an integrated approach

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1 Menopausal Management Options: an integrated approach v v Lifestyle HRT (hormone replacement therapy) the most efficacious treatment for climacteric symptoms v Non estrogenic alternatives : Conventional non- hormonal treatments Complementary and Alternative Medicines (CAM) Controindication for HRT,CVD risk Mild SNVG Older ages Personal beliefs G Bonaccorsi,Unife

2 Alternative and complementary medicine (CAM) a group of diverse medical and health care systems, practices, and products that are not generally considered to be part of conventional medicine Borrelli F,Ernst E,Maturitas 2010

3 G Bonaccorsi,Unife

4 Use of CAM and HRT for menopausal symptoms The majority of women (56.2%) reported they had not used any treatment for menopausal complaints during the previous 12 months. Of women who had used remedies to alleviate symptoms: 10.3% had used HRT alone, 26.7% had used CAM exclusively, while 6.8% had used CAM in conjunction with HRT. Overall, 33.5% had used CAM during the twelve months before questionnaire completion. G Bonaccorsi,Unife

5 The most popular products were herbal products (which included Cimicifuga and phytoestrogens extracted from Dioscorea, soy or other plants in the form of pills or decoctions) (41.4%) and additional soy in the diet (26.2%) G Bonaccorsi,Unife

6 Complementary and Alternative Medicine (CAM) treatments for improving quality of life during the menopausal v Come includere CAM in un algoritmo prescrittivo per la donna in postmenopausa? v Ruolo del ginecologo nel counselling informativo sulla CAM v Distinguere diverse classi terapeutiche v Possibile fenotipizzazione della paziente target? G Bonaccorsi,Unife

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10 Three groups of recognised interventions for relief of menopausal vasomotor symptoms

11 Obstet & Gynecol 1998;91:6-11

12 FOOD SUPPLEMENTS AND HERBAL MEDICINES Soy Black Cohosh Echinacea Blueberries EFFICACY? SAFETY? G Bonaccorsi,Unife

13 Fitoestrogeni La biochimica Fitoestrogeni Lignani enterodiolo Cumestani cumestrolo 4 metossicumestrolo enterolattone Isoflavoni (oltre 1000 tipi nel regno vegetale) Biocianina Formononetina metilazione Genisteina Daidzeina G Bonaccorsi Unife 13 G Bonaccorsi,Unife

14 Fitoestrogeni n Molecole presenti in diverse piante (alimentari e non) che presentano analogie strutturali e funzionali con gli estrogeni nativi presenti nell essere umano. n Sono classificati secondo differenti classi: isoflavoni, flavoni e lignani sono le principali classi di fitoestrogeni presenti nelle piante ad uso alimentare umano. G Bonaccorsi Unife 14

15 ISOFLAVONES: MECHANISM OF ACTION Genomic: Preferential link to ER beta: Link to ER alpha: - 100x less than Estradiol (Kuiper) Non genomic: Througout growth factors: - membrane receptors, EGF, VEGF, IGF1, PDGF CMO - UniFe Througout enzyme factors: - protein kinases, topoisomerases, 17β HSD, aromatases Adp from: R Trevaux, Phytotherapie: de la recherche à la pratique, N 12, 2001 Isoflavones act as agonist or antagonist at estrogen receptors G Bonaccorsi Unife 15

16 Summary of factors influencing activity of isoflavones (IF) in vivo n Type and dose of IF ingested n Type of intake (as isolated extract or as food matrix ) n Form of IF (glycon or aglicon) n Clinical biochemistry (e.g. levels of endogenous estrogens) n Biological biochemistry (e.g. receptor, enzymes) n Complexity of metabolism G Bonaccorsi Unife 16

17 Isoflavones: complexity of the metabolism HYDROLYSIS METABOLIZATION in jejunum by β-glycosidases by intestinal bacteria to equol and O-desmethylangolesin (O-DMA) ABSORPTION as aglycons (largely as genistein and daidzein). The absorption follows a saturation function, de-glycosilation is necessary for the intestinal absorption GLUCURONATION by liver cells BIOAVAILABILITY depends on the food composition and the enterohepatic circulatory efficiency PEAK BLOOD LEVEL EXCRETION reached 6-9 hrs after intake: to maintain sustained blood levels intake spread should be evenly distributed over the entire day. 20 to 50% of the ingested quantities are excreted within 24 hours G Bonaccorsi Unife 17

18 Main results 30 trials comparing phytoestrogens with control No significant difference overall in the frequency of hot flushes between a red clover extract and placebo Soy extract preparations globally showed inconsistent results, but three placebo-controlled studies showed a significant reduction in flush frequency 2007 There was a strong placebo effect in most trials with a reduction in frequency ranging from 1% to59% with placebo There was also no evidence that the treatments caused oestrogenic stimulation of the endometrium (an adverse effect) when used for up to two years. Authors conclusions There is no evidence of effectiveness in the alleviation of menopausal symptoms with the use of phytoestrogen treatments. G Bonaccorsi,Unife

19 Climacteric 2010;3: The role of complementary therapies in the management of the menopause, both for symptomatic relief and avoidance of long-term complications, remains highly controversial. The efficacy and safety of many complementary therapies have not been properly evaluated. No recognized international criteria for the design of clinical trials of alternative therapies as there are for standard medicines and medical devices. The same standards are applied as for medicinal products, but this might not be appropriate. Researchers often use products that are not chemically consistent, making comparison difficult with results from other studies. Botanical products may contain a variety of compounds whose individual and combined effects are unknown. There have been calls for tighter regulation Data from some of the better researched, phytoestrogen-containing preparations appear to demonstrate some benefits, not only for symptom relief, but also on the skeleton and cardiovascular system. There are as yet no hard data on major outcome measures such as coronary heart disease and fractures. G Bonaccorsi Unife 19

20 Fitoestrogeni e Sintomi Climaterici Risultati eterogenei e non conclusivi v v v v v v v v Diversi disegni sperimentali Variabilità degli Outcome clinici considerati Assenza di standardizzazione dei preparati in studio Assenza di Follow up adeguati Equolo produttrici? Complessità della metabolizzazione dei fitoestrogeni Eterogeneità dei campioni in studio Assenza di controllo dietetico G Bonaccorsi,Unife CMO

21 Soy n n Main Isoflavones: Daidzin, Genistin, Glycitin Menopause, studi RCT vs Placebo 12 settimane G Bonaccorsi Unife 21

22 Significant tendency in favour of soy G Bonaccorsi Unife 22

23 HRT versus placebo for hot flushes n In a Cochrane review of 24 trials involving 3329 participants, there was an overall reduction in hot flushes n 75% (95% CI 64 82%) with oral estrogen n 57% (95% CI 45 67%) with placebo MacLennan AH, et al. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No CD DOI: 23 G Bonaccorsi Unife / CD pub2

24 Vasomotor Symptoms G Bonaccorsi,Unife

25 MENOPAUSAL SYMPTOM EFFECTS Key recommendations v In postmenopausal women with distressing vasomotor symptoms, initial treatment with isoflavones is reasonable v The starting isoflavone dose should be 50 mg/day or higher, and therapy should be given for at least 12 weeks v If a woman responds to isoflavone supplementation,treatment can continue with monitoring for side effects; if a woman does not respond after 12 weeks, other treatment options should be discussed v A supplement containing natural S(Y)-equol may be effective for some women who do not have the capacity to produce equol. G Bonaccorsi,Unife

26 Complementary therapies for vasomotor symptoms High-quality studies to date have not consistently supported the efficacy of complementary or over-the-counter therapies in reducing severity or frequency of hot flushes or night sweats. Black cohosh and soy products are not superior to placebo in the treatment of hot flushes. G Bonaccorsi,Unife

27 Geller SE,2007 v St. John s wort (Hypericum) and black cohosh appear to be the most useful in alleviating mood and anxiety changes during menopause v Ginseng may be effective, but more research needs to be done v Kava holds promise for decreasing anxiety in peri- and postmenopausal women; however, women should be careful in the amount and duration of use v Ginkgo and valerian do not appear to be useful in reducing depression or anxiety in this population. G Bonaccorsi,Unife

28 Cimicifuga R. Costituenti chimici v La Cimicifuga possiede diversi costituenti chimici: (alcaloidi azotati, composti fenolici della categoria degli isoflavoni come la formononetina, acidi organici come l ac. isoferulico, triterpenoidi, e altri composti e sostanze volatili) v La formononetina e i triterpenoidi sono le 2 componenti bioattive più importanti. v L estratto alcolico isopropilico utilizzato in fitoterapia risulta privo della componente fitoestrogenica fenolica della formononetina. v I glucosidi triterpenici costituiscono la principale componente bioattiva presente nell estratto alcolico responsabili degli effetti terapeutici. I principali componenti triterpenoidi sono: - acteina - cimigenolo - gli esteri dell acido cinnamico - la 27-deossiacteina G Bonaccorsi,Unife

29 I glicosidi sono molecole costituite da due parti unite tra loro: lo zucchero xilosio e il triterpene del tipo cicloartenolo avente struttura steroidea. Struttura, simile a quella degli estrogeni che permette l interazione con i recettori ormonali: la particolare conformazione stereochimica potrebbe determinare quel legame selettivo tipico del meccanismo d azione di questo estratto 17-β-ESTRADIOLO GLICOSIDE TRITERPENICO G Bonaccorsi,Unife ZUCCHERO: XILOSIO AGLICONE: TRITERPENE CICLOARTEOLO

30 Estratto alcolico di Cimicifuga racemosa Effetti biologici antagonista competitivo degli estrogeni a livello dei recettori estrogenici con solo effetti di tipo inibitorio; non sono stati osservati effetti agonistici in assenza di estrogeni endogeni ( al contrario dei fitoestrogeni) agonista serotoninergico e dopaminergico a livello dei neurocettori di membrana del SNC capacità di modulare l azione di diversi neurotrasmettitori a livello del recettore GABA, del recettore dopaminergico D2, del recettore serotoninergico 5HT1A e dei recettori oppioidi mu (hmor) G Bonaccorsi,Unife

31 MECCANISMO D AZIONE G Bonaccorsi Unife 31

32 RCT,doppio cieco 66 donne Età media 53 anni Non effetti su funzione cognitiva di Trifoglio rosso e cimicifuga r. G Bonaccorsi Unife 32

33 Atrofia urogenitale Reed SD et al, Menopause,2008 Mean % parabasal cells Gli autori concludono che la supplementazione alimentare con preparati a base di cimicifuga r.,altri preparati vegetali e dieta ricca di soia non ha dimostrato efficacia nel trattamento dell atrofia vaginale valutata attraverso la citologia vaginale G Bonaccorsi,Unife

34 Fitoestrogeni e Osteoprotezione Le evidenze scien2fiche Studi biologici in vitro e su animale Studi epidemiologici/ osservazionali Trials clinici interventistici con : - alimenti a base di soia - isoflavoni concentrati Atmaca A.et al, Menopause,2008 G Bonaccorsi Unife 34

35 FITOESTROGENI E OSTEOPROTEZIONE Considerazioni Conclusive 2012 Evidenze da Meta- analisi di Trial clinici randomizza4 : Effe8o posi4vo degli Isoflavoni di Soia sulla densità minerale ossea (BMD) più eviden4 a livello di si4 scheletrici a maggior turn- over (colonna vertebrale). Aumen4 comunque inferiori a quelli o8enu4 con le terapie farmacologiche per l osteoporosi. Significa4va riduzione di markers del riassorbimento osseo Risulta4 significa4vi in campioni di donne in postmenopausa osteopeniche o osteoporo4che Assenza di studi clinici sulla prevenzione delle fra8ure Necessità di ulteriori studi clinici metodologicamente accura4 CMO

36 The American Journal of Medicine (2009) 122, Phytoestrogen supplements have a safe side effect profile In phytoestrogen supplement users,gastrointestinal side effects occur more often, compared with placebo or no treatment. Among phytoestrogen users in the investigated studies, there was no significant increase in rates of vaginal bleeding, endometrial hyperplasia, endometrial cancer, and breast cancer.

37 Fitoestrogeni e rischio cardiovascolare Antiatherogenic properties of flavonoids: implications for cardiovascular health. Mulvihill EE, Huff MW. Can J Cardiol Mar;26 Suppl A:17A-21A q Epidemiological studies suggest that higher flavonoid intake from fruits and vegetables is associated with decreased risk for the development of cardiovascular disease q Current evidence suggests that flavonoids may exert their effects through the improvement of cardiovascular risk factors q Flavonoids improve endothelial function, inhibit low-density lipoprotein oxidation, decrease blood pressure, reduce platelet aggregation and improve dyslipidemia. q Most studies have focused on cocoa, soy, and green and black tea. Recent evidence suggests that some polyphenols in their purified form, including resveratrol, berberine and naringenin, have beneficial effects on dyslipidemia in humans and/or animal models. G Bonaccorsi Unife 37

38 Endometrial Safety (soy and red clover) Majority of studies show no negative effect on endometrial tissue either in vivo /in vitro Higher consumption of isoflavones in the diet may even be linked to reduced risk for endometrial cancer Concern about the endometrium comes only from 1 long term study G Bonaccorsi Unife 38

39 q? Relazione fra fitoestrogeni e prevenzione primaria del cancro della mammella q? Uso nelle donne con controindicazioni alla HT per il trattamento dei sintomi vasomotori q? Fitoestrogeni e rischio di recidiva di ca mammario q? Interazione tra fitoestrogeni e tamoxifene G Bonaccorsi Unife 39

40 Isoflavones and Cancer Biological evidences for a protective effect Estrogen partial agonism/antagonism (α and β estrogen receptors) Increase of sex hormone-binding globulin levels Inhibition of tyrosine and other protein kinases and angiogenesis Inhibition of several enzymes (3 β HSD,17 β HSD1,5alfa reductase, topoisomerase 1 and 2,aromatase) Alteration of growth factor activity Inhibition of specific events in the cell cycle, G1/S (TGFβ signaling) and G2/M (DNA topoisomerase) Precipitation of apoptosis (both in vitro and in vivo) Induction of cell differentiation Anti-oxidants in vitro and in vivo G Bonaccorsi Unife 40 Adlercreutz H,2002, The Lancet Oncology

41 Nutrition Journal 2008, 7:17 Currently there is little evidence to suggest that any potential weak estrogenic effects of dietary isoflavones have a clinically relevant impact on breast tissue in healthy women. Limited data suggest this is also the case for breast cancer survivors it seems unlikely that isoflavone consumption at dietary levels (i.e. <100 mg/day) elicits adverse breast cancer-promoting effects in healthy women or breast cancer survivors not undergoing active treatment. Currently there are no data to support the idea that soy foods or isoflavone supplements improve the prognosis of breast cancer patients G Bonaccorsi Unife 41

42 v Overall, current research demonstrates that phytoestrogens are effective in reducing the intensity of hot flushes, and some phytoestrogen combinations result in a decreased frequency. v Certain phytoestrogens have also been shown to decrease vaginal atrophy, improve sleep and cognition, and positively affect bone health. v Even though initial research was generally unconvincing, the more recent evidence reviewed here is rather positive. v In terms of safety and reports of adverse reactions, trials have not shown an increase in breast cancer risk or increase in endometrial hyperplasia following phytoestrogen use, but trials explicitly designed to find neoplasia have not been reported. v Moreover,unlike hormone therapy,isoflavones and lignans may not increase clotting risk in postmenopausal women v Phytoestrogens may provide a safe and partially effective alternative to HT. G Bonaccorsi,Unife