Phytoestrogens in postmenopause: the state of the art from a chemical, pharmacological and regulatory perspective

Abstract

Phytoestrogens represent a diverse group of non-steroidal natural products, which seem to have some oestrogenic effects and are often marketed as food supplements. Population exposed to phytoestrogens is potentially increasing, in part because an unfavourable risk-benefit profile of Hormone Replacement Therapy (HRT) for prolonged treatments (e.g., osteoporosis prevention) highlighted by the publication of the Women Health Initiative (WHI) trial in 2002, but also because many post-menopausal women often perceived phytoestrogens in food supplements as a safer alternative than HRT. Despite of increasing preclinical and clinical studies in the past decade, appealing evidence is still lacking to support the overall positive risk-benefit profile of phytoestrogens. Their status as food supplements seems to discourage studies to obtain new evidence, and the chance to buy them by user's initiative make it difficult to survey their prevalence and pattern of use. The aim of the present review is to: (a) outline the clinical scenario underlying the increased interest on phytoestrogens, by overviewing the evolution of the evidence on HRT and its main therapeutic goals (e.g., menopausal symptoms relief, chemoprevention, osteoporosis prevention); (b) address the chemical and pharmacological features (e.g. chemical structure, botanical sources, mechanism of action) of the main compounds (e.g., isoflavones, lignans, coumestans); (c) describe the clinical evidence on potential therapeutic applications; (d) put available evidence on their riskbenefit profile in a regulatory perspective, in light of the recent regulation on health claims of food supplements.

Fig. (1)

Biosynthesis of isoflavones.

Fig. (2)

Structures of metabolized isoflavones.

Fig. (3)

Biosynthesis of lignans.

Fig. (4)

Structures of metabolized lignans.

Fig. (5)

Biosynthesis of coumestans.

Fig. (6)

Binding mode and ligand interaction diagram of Estradiol (A and B respectively) and Genestein (C and D respectively) in ERα (PDB code: 1A52 and 1X7R). In A and C the protein is represented as line and cartoon, the ligand as stick. H-bonds are represented as yellow dotted lines. In B and D the interactions are represented as: violet arrow (H-bond), green arrow (Π-Π stacking), ciano sphere (polar), green sphere (Hydrophobic), red sphere (Charged positive) and blue sphere (Charged negative).

Fig. (7)

Binding mode and ligand interaction diagram of Estradiol (A and B respectively) and Genestein (C and D respectively) in ERβ (PDB code: 3OLS and 1X7J). In A and C the protein is represented as line and cartoon, the ligand as stick. H-bonds are represented as yellow dotted lines. In B and D the interactions are represented as: violet arrow (H-bond), green arrow (Π-Π stacking), ciano sphere (polar), green sphere (Hydrophobic), red sphere (Charged positive) and blue sphere (Charged negative).

Fig. (8)

Structures of other estrogenic compounds.

Fig. (9)

Publication trend (from 1945 to 2011) for articles concerning phytoestrogens, classified for preclinical and clinical studies. Data concerning 2012 are not showed because they are incomplete at the time the search strategy was performed.