1. Introduction
Menopause results from reduced secretion of the ovarian hormones estrogen and progesterone, which takes place as the finite store of ovarian follicles is depleted. Women in the menopausal transition and postmenopausal period are affected by vasomotor symptoms, urogenital atrophy, sexual dysfunction, somatic symptoms, cognitive difficulty, sleep disturbance, and psychological problems. Some of these effects such as vasomotor symptoms are closely associated with estrogen deficiency, but the exact mechanisms underlying the other symptoms are not fully understood [
1]. Postmenopausal women are also at increased risk for cardiovascular morbidity [
2] as a net effect of central obesity [
3], dyslipidemia [
4], hypertension [
5], and diabetes [
6] partly induced by estrogen deficiency.
Flavonoids are a class of polyphenolic compounds with significant human health benefits [
7]. Some of the flavonoids such as the flavan-3-ols catechin and epicatechin polymerize to form tannins. Tannins are plant secondary metabolites that can be hydrolysable or condensed. The condensed tannins are also known as proanthocyanidins [
8,
9]. They are widely present in the plant kingdom, for example, in fruits, berries, nuts, seeds, and bark of pine trees [
10,
11,
12]. Proanthocyanidins are oligomers or polymers of flavan-3-ols, where the monomeric units are linked mainly by C-4 to C-8 bonds, although less frequently C-4 to C-6 linkages can also be found. These types of linkages lead to the formation of the so-called B-type proanthocyanidins. A-type proanthocyanidins, on the other hand, are characterized by an additional bond between C-2 → C-7 of the basic flavan-3-ol units [
13]. Proanthocyanidins are composed of different flavan-3-ol subunits, known as proanthocyanidin monomers or catechins. The most common monomeric units are the diastereomers of (epi)catechin, (epi)afzelechin, and (epi)gallocatechin (
Figure 1).
In recent years, considerable attention has been paid to proanthocyanidins due to the potential beneficial effects on human health, including antioxidative, cardio-protective anti-inflammatory, and anticancer properties [
13,
14,
15,
16]. Some reviews have also been published on the effects of proanthocyanidins [
9,
13], however, there still seems to be no reviews on the effects for middle-aged and elderly women. This review therefore aims to highlight aspects of the effects of food-derived proanthocyanidins for middle-aged and elderly women’s health.
4. Discussion
We show the scheme for the relationship between the effect of proanthocyanidins and disease field in
Figure 2.
Menopausal disorders are caused by estrogen deficiency. Hormone replacement therapy (HRT) remains one of the most effective therapies for vasomotor symptoms that are representative of menopausal symptoms, and it could be beneficial for young and recently postmenopausal women in relation to improvements in cardiovascular health [
48]. Soy isoflavones are well known as phytoestrogens and have been heavily reported with regard to the clinical efficacy for menopausal symptoms [
49,
50]. In this review, we have reported that two types of proanthocyanidins, derived from grape seed and pine bark, improved menopausal symptoms. Terauchi et al. proposed that the mechanism of alleviative effect for vasomotor symptoms is generally attributed to their antioxidant activities, although they do not bind to estrogen receptors, and also have considered that their hypnosedative and anxiolytic activities might partly explain the effects of proanthocyanidins acting through gamma amino butyric acid (GABA)A receptors [
51]. Moreover, anxiolytic and depressive activities of proanthocyanidins have been reported, involving the central monoaminergic neurotransmitter systems [
52] and inhibiting the expressions of the proinflammatory cytokines, iNOS and COX-2 in the hippocampus [
53]. In a prospective cohort study, it has also been revealed that higher proanthocyanidin intakes were associated with lower depression risk, with the highest intake group taking up to 160–179 mg of proanthocyanidins per day. The amount was approximated to the result of intervention trials as mentioned above.
Regarding cancer prevention, laboratory experiments using animal models or cultured human cell lines support a potential role of polyphenols in cancer prevention through antioxidant, immunomodulatory, anti-inflammatory, anti-angiogenic, and pro-apoptotic properties [
54,
55]. However, the effect of polyphenol intake on disease prevention in humans is difficult to predict, partly because in vivo studies often employed doses or concentrations far beyond those achievable by human diet. The prevention of breast and endometrial cancer is of particularly high significance for elderly women. In two cohort studies, it was revealed that the intake of proanthocyanidins was associated with significantly decreased breast and endometrial cancer risk. Proanthocyanidins have antioxidant and antiangiogenesis effects and may influence signal transduction and inhibit the action of DNA topoisomerases [
56,
57]. Although the bioavailability of higher molecular weight proanthocyanidins is lower, they are characterized by a higher gastric stability [
58] and a higher potential scavenger activity [
59]. In fact, bioavailability of proanthocyanidins (in monomeric, oligomeric, and polymeric forms of flavan-3-ols) is influenced by their degree of polymerisation; monomers are readily absorbed in the small intestine, whereas oligomers and polymers need to be biotransformed by the colonic microbiota because they are resistant to acid hydrolysis in the stomach [
58]. Therefore, phenolic metabolites, rather than the original high-molecular weight compounds found in foods, may be responsible for the health effects derived from proanthocyanidin consumption [
60], especially those with higher degree of polymerization. In experimental studies, the microbial metabolites of proanthocyanidins still bearing a free phenolic acid showed protective effects against oxidative stress and obesity [
61,
62], the major risk factors for endometrial cancer. Culter et al. reported that lung cancer incidence was inversely associated with intakes of proanthocyanidins. In another animal experiment, it was revealed that administration of grape seed proanthocyanidins to athymic nude mice by oral gavage (5 days per week) markedly inhibited the growth of s.c. A549 and H1299 lung tumor xenografts, which was associated with the induction of apoptotic cell death, increased expression of Bax, reduced expression of anti-apoptotic proteins, and activation of caspase-3 in tumor xenograft cells [
23]. These results suggest that proanthicyanidins may represent a potential component for lung cancer.
Evidence from many short-term trials in humans has suggested that flavonoids and, in particular, flavanol monomers and procyanidin may have a beneficial effect on blood pressure in humans [
63]. In this review, we show the effect of grape seed proanthocyanidin on blood pressure in elderly Japanese women and the relation between proanthocyanidin intake and incidence of hypertension in a large prospective cohort of women. Odai et al. considered that grape seed proanthocyanidin improving blood pressure without affecting flow-mediated dilation indicates that the antioxidant effects of proanthocyanidins could regulate vascular tone, not through NO release, but by other endothelial responses, which results in blood pressure reduction; one study on hypertensive rats that supports their results showed the positive association between reactive oxygen species (ROS) level and pulse wave velocity, arterial wall thickness, and collagen deposition and the beneficial effects of antioxidants on arterial stiffness and remodeling [
64], implying that the antioxidant capacity of grape seed proanthocyanidin could contribute to decreased ROS levels and improved vascular elasticity. Evidence for the potential mechanism by which proanthocyanidin would affect blood pressure could also be related to the inhibition of the angiotensin-converting enzyme [
65].
Epidemiologic data suggest that dietary flavonoids may have beneficial cardiovascular effects in human populations. Several prospective studies have reported statistically significant inverse associations between total flavonoid intake or the intake of specific classes of flavonoids and cardiovascular disease (CVD) incidence or mortality [
66,
67]. In this review, we revealed that incremental elastic modulus (Einc) and pulse wave velocity (PWV) also significantly improved by oral intake of grape seed proanthocyanidins, and consumption apple proanthocyanidins produced a statistically significant decrease in oxidized low-density lipoprotein/beta2-glycoprotein I complex (oxLDL-b2GPI) related to atherosclerosis. These results support the fact that proanthocyanidins affect cardiovascular health. In cohort studies, the intake of proanthocyanidins has also been reported to significantly reduce CVD mortality for middle-aged and elderly women. The cardioprotective effects of proanthocyanidins have been highlighted by several studies regarding the mechanism: oxidative stress, cardiomyocytes and the endothelium, anti-inflammatory effects, metabolic effects, etc. [
68]. These beneficial effects appear to be mediated by various signaling pathways and mechanisms acting either independently or synergistically.
Overweight and obesity are recognized as important risk factors for type 2 diabetes (T2D). Some cohort studies for elderly women have been investigated with regards to diabetes mellitus and obesity and have revealed that the intake of proanthocyanidins is inversely associated with abdominal obesity or overweight. Yang et al. proposed that proanthocyanidins lower hepatic glucose production by activating adenosine monophosphate(AMP)-activated protein kinase and/or insulin-signaling pathways, play a role in protecting pancreatic β cells from oxidative stress, and promote insulin secretion and β-cell survival, and the actions of proanthocyanidins on liver and pancreatic β cells could lower blood glucose and reduce metabolic and oxidative stress on the islets to enhance glucose homeostasis, which could be of long-term benefit to overall metabolic health [
69]. Regarding the hypertension, cardiovascular, and obesity fields, the highest intake group consumed 168–524 mg of proanthocyanidins as a daily average amount in each cohort study reported in this review. These results may suggest that the effective intake of proanthocyanidins for these diseases may be larger than that for menopausal symptoms.
Osteopenia is an important predictor of osteoporosis as it is characterized by low bone mineral density (BMD) [
70]. Because osteoporosis has also become an important factor in morbidity and mortality in elderly women, its prevention is therefore of utmost importance in this age group. Many studies have examined the associations between flavonoids and bone health [
71,
72,
73]; however, most of them, including randomized controlled trials (RCTs), have focused primarily on the isoflavone subclass, which is mainly contained in soy foods. In this review, pine bark proanthocyanidin, not estrogenic compound, supplementation in postmenopausal osteopenic women has been shown to produce favorable effects on bone markers. Moreover, in a cohort study, dietary proanthocyanidin intake was positively associated with BMD in middle-aged and elderly women. The inhibition of receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL)-dependent osteoclast differentiation caused by proanthocyanidins was indicated by studies in vitro [
74]. Animal experimental results also suggested that proanthocyanidins can promote bone formation [
75]. Proanthocyanidins may be expected for the prevention of osteoporosis instead of soy isoflavones.
A urinary tract infection (UTI) is common and increasingly difficult to treat because of the rising rates of antibiotic resistance [
76,
77]. Approximately 60% of women will experience up to one UTI in their lifetimes. Cranberry consumption has been evaluated as a strategy for reducing clinical UTI recurrence in women with a recent history of a UTI [
78,
79]. In this review, we have shown that the consumption of cranberry juice or cranberry powder containing proanthocyanidins lowered the incidence of UTI for elderly women. The proanthocyanidins in cranberry have been reported to inhibit the growth of several pathogenic bacteria, such as uropathogenic
Escherichia coli, cariogenic
Streptococcus mutans, and oxacillin-resistant
Staphylococcus aureus [
80]. The cranberry proanthocyanidins, consisting primarily of epicatechin tetramers and pentamers with at least one A-type linkage, have been found to be active against the pathogenic bacteria. In addition, the daily intake of 65% cranberry juice is recommended to prevent recurrent cystitis for postmenopausal women in the Guideline in The Japanese Association for Infectious Disease/Japanese Society of Chemotherapy (JAID/JSC) Guidelines for Infection Treatment—Urinary Tract Infection.
Chronic kidney disease (CKD) represents a growing public health issue [
81]. Oxidative stress, atherogenesis, nitric oxide homeostasis, and endothelial function play important roles in the pathogenesis of this disease [
82,
83,
84,
85,
86]. Ageing is associated with structural and functional changes in the kidneys [
87], resulting in impaired renal function [
88]. Cystatin C provides early indications of renal dysfunction [
89]. Ivey et al. indicated in a cohort study that higher intake of proanthocyanidins lowered the plasma cystatin C level. There is direct evidence that proanthocyanidins can specifically improve renal health in animal models by reducing oxidative stress, improving antioxidant defense potential, and reducing oxidative renal injury [
56,
90,
91]. Proanthocyanidins may contribute to the prevention of severe CKD.
Abnormal facial pigmentation such as chloasma (melasma) is often of great cosmetic importance to women. Chloasma is a common acquired symmetrical hypermelanosis characterized by irregular light to dark brown macules and patches on sun-exposed areas of the skin. Although the etiology is unknown, several etiogenic factors have been implicated, including genetic factors, UV exposure, pregnancy, hormonal therapies, cosmetics, phototoxic drugs, and antiseizure medications [
92]. In this review, we have reported that grape seed proanthocyanidins and cranberry proanthocyanidin with vitamin A, C, and E improved chloasma in an intervention study. Yamakoshi et al. considered that grape seed proanthocyanidins were likely to inhibit melanogenesis or even melanocyte proliferation only in the chloasma area. The human skin is constantly exposed to UV radiation. UV radiation generates reactive oxygen species (ROS) and leads to oxidative stress. This causes a cascade of erythema and inflammatory reactions, which may be considered as crucial factors affecting the pathogenesis of melasma. Proanthocyanidin has been proven to have a significant free radical scavenging activity in vitro and anti-edema effects in vivo [
93]. Additionally, the oral intake of pine bark proanthocyanidins have led to significant reduction in the pigmentation of age spots in photoaged facial skin. The results may be attributed to the antioxidative and anti-inflammatory effects of proanthocyanidins.
The physical, chemical, and biological features of proanthocyanidins depend largely on their structure including the type of flavan-3-ol, particularly on their degree of polymerization. We failed to evaluate the structure–activity relationship (SAR) in each effect because of not so many results of the intervention trial. Proanthocyanidins functioning in terms of absorption and metabolism in human is not yet fully understood. The intestinal cell wall is permeable to proanthocyanidin dimers and trimers, as shown in both in vitro [
94] and in vivo experiments [
95]. Proanthocyanidins with a degree of polymerisation (DP) below 3 are depolymerised into mixtures of epicatechin monomers and dimers in the acidic environment of the stomach [
94] and absorbed by the small intestine [
94,
95]. However, it is also proposed that a food bolus has a buffering effect, making the acidic conditions milder than that required for proanthocyanidin breakdown. Although proanthocyanidin dimers B1 and B2 can be detected in human plasma [
95,
96], their absorption is minor, estimated to be more than 100-fold lower than that of the corresponding flavan-3-ol monomers [
95]. The cell layer in the intestines is also permeable to oligomeric proanthocyanidins but not polymeric ones [
94,
95]. Polymeric proanthocyanidins with a DP up to 10 move to the small intestines intact and are mainly degraded by colonic microflora in the cecum and large intestine [
97]. Further research is needed to better investigate the active metabolites of proanthocyanidins and detail the mechanism in humans.
