**Use of Phytoestrogens for the Treatment of Psychiatric Symptoms Associated with Menopause Transition**

[47] Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, Agerman K, Haapasalo A, Nawa H, Aloyz R, Ernfors P, Castren E. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. Journal of Neuroscience. 2003;**23**:349-357. DOI:

[48] Malberg JE, Platt B, Rizzo SJ, Ring RH, Lucki I, Schechter LE, Rosenzweig-Lipson S. Increasing the levels of insulin-like growth factor-I by an IGF binding protein inhibitor produces anxiolytic and antidepressant-like effects. Neuropsychopharmacology.

[49] Hoshaw BA, Hill TI, Crowley JJ, Malberg JE, Khawaja X, Rosenzweig-Lipson S, Schechter LE, Lucki I. Antidepressant-like behavioral effects of IGF-I produced by enhanced serotonin transmission. European Journal of Pharmacology. 2008;**594**:109-116. DOI: 10.1016/j.

[50] Pomierny-Chamioło L, Poleszak E, Pilc A, Nowak G. NMDA but not AMPA glutamatergic receptors are involved in the antidepressant-like activity of MTEP during the forced

[51] Benmansour S, Arroyo LD, Frazer A. Comparison of the antidepressant-like effects of estradiol and that of selective serotonin reuptake inhibitors in middle-aged ovariectomized rats. Frontiers in Aging Neuroscience 2016;**8**:311. DOI: 10.3389/fnagi.2016.00311 [52] Fedotova IuO. Behavioral effects of m-CPP and ketanserine during ovarian cycle in female rats. Eksperimental'naia i klinicheskaia farmakologiia. 2010;**73**(11):6-9

[53] Pilar-Cuéllar F, Vidal R, Pazos A. Subchronic treatment with fluoxetine and ketanserin increases hippocampal brain-derived neurotrophic factor, β-catenin and antidepressant-like effects. British Journal of Pharmacology. 2012;**165**(4b):1046-1057. DOI:

[54] Gaynes BN, Jackson WC, Rorie KD. Major depressive disorder in the primary care setting: Strategies to achieve remission and recovery. The Journal of Family Practice.

[55] Pandey DK, Bhatt S, Jindal A, Gautam B. Effect of combination of ketanserin and escitalopram on behavioral anomalies after olfactory bulbectomy: Prediction of quick onset of antidepressant action. Indian Journal of Pharmacology. 2014;**46**(6):639-643. DOI:

[56] Kranz GS, Rami-Mark C, Kaufmann U, Baldinger P, Hahn A, Höflich A, Savli M, Stein P, Wadsak W, Mitterhauser M, Winkler D, Lanzenberger R, Kasper S. Effects of hormone replacement therapy on cerebral serotonin-1A receptor binding in postmenopausal women examined with [carbonyl-11C]WAY-100635. Psychoneuroendocrinology

[57] Harlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, Sherman S, Sluss PM, de Villiers TJ; STRAW 10 Collaborative Group. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging.

Menopause. 2012;**19**(4):387-395. DOI: 10.1097/gme.0b013e31824d8f40

swim test in mice. Pharmacological Reports. 2010;**62**(6):1186-1190

0270-6474/02/220349-09

80 A Multidisciplinary Look at Menopause

ejphar.2008.07.023

10.1111/j.1476-5381.2011.01516.x

2015;**64**(9):S4–S15

10.4103/0253-7613.144935

2014;**45**:1-10. DOI: 10.1016/j.psyneuen.2014.03.004

2007;**32**:2360-2368. DOI: 10.1038/sj.npp.1301358

Erika Estrada-Camarena, Carolina López-Rubalcava, Brenda Valdés-Sustaita, Gabriel Sinhue Azpilcueta-Morales and Eva María González-Trujano

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69541

### **Abstract**

Menopause transition is recognized as a vulnerable period in women life to develop or aggravate symptoms of psychiatric disorders. Several treatments including antidepressants and hormonal restitution with estrogens have been suggested to ameliorate the symptoms. Also, in this period of life is frequent the use of other drugs to treat is also frequent the use of other drugs to treat comorbid pathologies that might even increase the risk of drug-drug interactions. Literature reports that some phytochemicals with estrogenic activity have beneficial effects during menopausal transition without collateral events. This chapter shows evidence about the use of phytoestrogens as an alternative therapy for the treatment of some psychiatric symptoms associated with the menopausal transition. Data derived from preclinical research related to the use of classical phytoestrogens (isoflavones), considering the beneficial effects, as well as adverse events, are discussed. Also, the use of polyphenols and organosulfurate compounds as an alternative for the treatment of anxiety- and depressive-like behavior as well as fibromyalgia is included. A narrative review was conducted using bibliography reporting the use of isoflavones (genistein, daidzein, equol), coumestans or lignans for the reduction of depressive-like or anxiety-like behavior. Furthermore, it is described if the use of this compounds impact in other signs of menopause, i.e. vasomotor and osteoporosis. In addition, due to the high frequency of comorbid pathologies as diabetes mellitus, dyslipidemia or metabolic syndrome with psychiatric disorders, the use of these phytochemicals is discussed.

**Keywords:** menopause, polyphenols, glycosinolates, phytoestrogens

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **1. Introduction**

With the increase of life expectancy, women potentially spend the last third of their lives in post-menopause. Most of the menopausal women suffer from a variety of symptoms such as hot flashes, night sweats, mood swings, insomnia, vaginal dryness and osteoporosis [1, 2]. Also, the menopause transition could be a vulnerable period to develop some diseases related to mental disorders (i.e., anxiety and depression) and chronic non-degenerative pathologies (metabolic diseases) in addition to menopausal symptoms [3, 4]. This situation implies that women that transit in this period of life could be vulnerable to develop co-morbidities leading to a complex medical management due to the elevated cost and possible pharmacological interactions.

Hormone replacement therapy is considered the first line of treatment for menopause symptoms, mainly vasomotor and night sweats. However, many women refuse it because of their association with increased risk of breast cancer and are considering botanical products or dietary supplements as therapy because they are regarded as safer products [1, 2, 5]. For example, black cohosh is widely employed for hot flashes and mood disorders; others are compounds with estrogenic activity (phytoestrogens) as soy food products, red clover, kudzu, hops, licorice, rhubarb, yam and chasteberry [1].

The use of functional food and nutraceuticals became common to treat menopause symptoms [2]. The term "nutraceutical" combines two words—"nutrient" (a nourishing food component) and "pharmaceutical" (a medical drug). It is defined as "any substance that may be considered a food or part of it that provides medical or health benefits, including the prevention and treatment of diseases." These products include isolated nutrients, dietary supplements and diets genetically engineered "designed" foods, botanical products and processed foods such as cereals, foods and beverages [6]. A nutraceutical is demonstrated to have a physiological benefit or provide protection against chronic disease [6]. On the other hand, functional food according to American Dietetic Association, "functional" implies that the food possesses some identified value leading to health benefits, including reducing the risk of adverse effects for a person consuming it [7].

Nutraceuticals and functional food are classified in several manners taken into account their content of specific food, properties (anti-cancer, positive influence on blood lipid profile, antiinflammatory, osteogenic or bone protective) or chemical structure [6]. Both nutraceuticals and functional food contain active compounds called phytochemicals that confer their properties. Phytochemicals are products of the secondary metabolism of a plant which are biologically active in humans and other animal species playing a greater beneficial role in health more than only nutritional properties. These products are part of the defense system and plants' protection [8], and in humans, they have activity in several systems such as the digestive, immune, cardiovascular, endocrine and central nervous system [6, 8], among others. Also, phytochemicals confer organoleptic properties to vegetables and fruits [8].

Phytochemicals are classified into four groups according to their impact on health [9, 10]:

The distribution of phytochemicals' sources could be at the same time diffuse and copious as well as specific depending on the product, for example, carotenoids are frequently found in several products (carrots, tomato, orange, mango, pumpkin, guava), whereeas glycosinolates are found only in cruciferous (broccoli, brussel sprout, cabbage, horseradish, rutabaga) [8]. The concentration of the phytochemical could vary depending on the morphological factors: skin, seed, pulp, peel, leaves, also on agronomic factors: weather, agricultural soil, technical procedure, physiological stress; and postharvest: maturity, processing and storage, among the others [8].

### **2. Phytochemicals: polyphenols**

**1. Introduction**

82 A Multidisciplinary Look at Menopause

hops, licorice, rhubarb, yam and chasteberry [1].

**1.** Terpenoids (i.e., carotenoids and phytosterols)

person consuming it [7].

With the increase of life expectancy, women potentially spend the last third of their lives in post-menopause. Most of the menopausal women suffer from a variety of symptoms such as hot flashes, night sweats, mood swings, insomnia, vaginal dryness and osteoporosis [1, 2]. Also, the menopause transition could be a vulnerable period to develop some diseases related to mental disorders (i.e., anxiety and depression) and chronic non-degenerative pathologies (metabolic diseases) in addition to menopausal symptoms [3, 4]. This situation implies that women that transit in this period of life could be vulnerable to develop co-morbidities leading to a complex medical management due to the elevated cost and possible pharmacological interactions. Hormone replacement therapy is considered the first line of treatment for menopause symptoms, mainly vasomotor and night sweats. However, many women refuse it because of their association with increased risk of breast cancer and are considering botanical products or dietary supplements as therapy because they are regarded as safer products [1, 2, 5]. For example, black cohosh is widely employed for hot flashes and mood disorders; others are compounds with estrogenic activity (phytoestrogens) as soy food products, red clover, kudzu,

The use of functional food and nutraceuticals became common to treat menopause symptoms [2]. The term "nutraceutical" combines two words—"nutrient" (a nourishing food component) and "pharmaceutical" (a medical drug). It is defined as "any substance that may be considered a food or part of it that provides medical or health benefits, including the prevention and treatment of diseases." These products include isolated nutrients, dietary supplements and diets genetically engineered "designed" foods, botanical products and processed foods such as cereals, foods and beverages [6]. A nutraceutical is demonstrated to have a physiological benefit or provide protection against chronic disease [6]. On the other hand, functional food according to American Dietetic Association, "functional" implies that the food possesses some identified value leading to health benefits, including reducing the risk of adverse effects for a

Nutraceuticals and functional food are classified in several manners taken into account their content of specific food, properties (anti-cancer, positive influence on blood lipid profile, antiinflammatory, osteogenic or bone protective) or chemical structure [6]. Both nutraceuticals and functional food contain active compounds called phytochemicals that confer their properties. Phytochemicals are products of the secondary metabolism of a plant which are biologically active in humans and other animal species playing a greater beneficial role in health more than only nutritional properties. These products are part of the defense system and plants' protection [8], and in humans, they have activity in several systems such as the digestive, immune, cardiovascular, endocrine and central nervous system [6, 8], among others.

Also, phytochemicals confer organoleptic properties to vegetables and fruits [8].

**2.** Phenols (i.e., flavonoids, phenolic acids, tannins, stilbens and curcuminoids)

Phytochemicals are classified into four groups according to their impact on health [9, 10]:

Polyphenols can be found in a large variety of food mainly of vegetable origin. They constitute the major group of natural compounds known (around 8000 identified) in the plant kingdom [11]. These compounds result of the secondary metabolism of carbon by the acetate-malonate and shikimate pathways. They are characterized by the presence of phenolic structures with a potent antioxidant activity that confers protection to plants against oxidative stress, ultraviolet radiation and other harmful factors of the environment such as pollutants and pathogens [12]. There are a wide variety of polyphenols but, in general, they have been classified into two groups according to their chemicals properties: flavonoids and non-flavonoids (**Figure 1**).

**Figure 1.** The scheme illustrates the main polyphenols and their division. Phytoestrogens are products of the metabolism of polyphenols: isoflavones and coumenstans are flavonoids, whereas lignans and stilbens are non-flavonoids.

The flavonoid group includes compounds whose structure contains the flavan nucleus (diphenyl propane; C:15: C3, C6, C3), such as anthocyanidins, proanthocyanidins, catechins, flavones, flavonols, flavanones, isoflavones and coumestans (**Figure 1**). The non-flavonoids group includes phenolic acids, phenolic amides and other polyphenols, such as tannins, lignans and stilbene compounds (**Figure 1**). Polyphenols, flavonoids and nonflavonoids have biological importance and are considered as nutraceuticals, not only for their antioxidant effect but also for their beneficial effects on health such as cardiovascular, diabetes and neurodegenerative protection, cancer prevention and anti-infection effect [11].

Recently, it has been determined that some polyphenols, especially isoflavones, flavonols, anthocyanidins, lignans, stilbenes and coumestans, have estrogenic activities, for which they have been denominated as phytoestrogens.

### **3. Phytoestrogens**

Phytoestrogens are non-steroidal compounds that have a unique similarity in molecular weight and the arrangement of aromatic rings with hydroxyl groups to the cyclopentanoperhydrophenanthrene of 17β-estradiol (the most important endogenous estrogen; **Figure 2**).

**Figure 2.** Phytoestrogens. The figure illustrates comparatively the chemical structure of 17β-estradiol and some phytoestrogens. Phytoestrogens are non-steroidal compounds that have a unique similarity in molecular weight and the arrangement of aromatic rings with hydroxyl groups to the cyclopentanoperhydrophenanthrene of 17β-estradiol.

The types of phytoestrogens are isoflavones, lignans, coumestans, ellagitannins and stilbens [13–15]. **Figure 3** shows the main sources of phytoestrogens and the phytochemicals with estrogenic properties. The primary sources of lignans are flaxseed, whole grain cereal and some beverages, such as coffee, tea and wine [15]. For isoflavones are legumens such as soybeans and peanuts, chickpeas and kudzu, lupine, fava, alfalfa, peanuts and chickpeas [15]. In the case of clover alfalfa and soybean sprouts, these are sources of coumestans [13]. Ellagitannins are abundant in fruits, nuts and seeds such as pomegranate, black raspberries, strawberries, walnuts and almonds [16]. The main source of stilbens such as revestratrol is the red wine and peanuts [15].

The flavonoid group includes compounds whose structure contains the flavan nucleus (diphenyl propane; C:15: C3, C6, C3), such as anthocyanidins, proanthocyanidins, catechins, flavones, flavonols, flavanones, isoflavones and coumestans (**Figure 1**). The non-flavonoids group includes phenolic acids, phenolic amides and other polyphenols, such as tannins, lignans and stilbene compounds (**Figure 1**). Polyphenols, flavonoids and nonflavonoids have biological importance and are considered as nutraceuticals, not only for their antioxidant effect but also for their beneficial effects on health such as cardiovascular, diabetes and neuro-

Recently, it has been determined that some polyphenols, especially isoflavones, flavonols, anthocyanidins, lignans, stilbenes and coumestans, have estrogenic activities, for which they

Phytoestrogens are non-steroidal compounds that have a unique similarity in molecular weight and the arrangement of aromatic rings with hydroxyl groups to the cyclopentanoperhydrophenanthrene of 17β-estradiol (the most important endogenous estrogen; **Figure 2**).

**Figure 2.** Phytoestrogens. The figure illustrates comparatively the chemical structure of 17β-estradiol and some phytoestrogens. Phytoestrogens are non-steroidal compounds that have a unique similarity in molecular weight and the arrangement of aromatic rings with hydroxyl groups to the cyclopentanoperhydrophenanthrene of 17β-estradiol.

degenerative protection, cancer prevention and anti-infection effect [11].

have been denominated as phytoestrogens.

**3. Phytoestrogens**

84 A Multidisciplinary Look at Menopause

It is important to note that the beneficial actions of phytoestrogens are mostly given by the estrogenic/anti-estrogenic effect dependent on the resultant concentration of the metabolism

**Figure 3.** Phytoestrogens and their main food or beverage source. Ellagitannins, lignans and isoflavones require of microbiota biotransformation to release an active compound (urolithins A and B, enteronolactone or Equol, respectively) that produces their estrogen-like effects on different tissues. In contrast, stilbens and coumestans production appears to be independent of microbiota.

of phytoestrogens. It is known that phytoestrogens are mostly as glycosides and that only the aglycone fraction is bio-available to produce biological effects [17]. Some phytoestrogens, such as isoflavones, ellagitannins and lignans, require the action of gut bacterial enzymes to produce equol, urolithins and enterolignans, respectively [16, 18, 19]. These subproducts have more bioavailability and have more estrogenic/anti-estrogenic and anti-oxidant, anti-inflammatory and anti-proliferative activity than their precursors [20]. Furthermore, it is proposed that the biotransformation of isoflavones, ellagitannins and lignans by intestinal microbiota is essential in protection against menopausal symptoms. Also against certain chronic diseases, such as cancer, cardiovascular disease and osteoporosis [15], suggesting that the main discrepancies between a successful treatment versus lack of effect could be explained by the low bioavailability of phytoestrogens [21].

In this line, several reports indicate that coumestans—coumestrol and methoxycoumestrol show estrogenic activity; the most active compound of isoflavones is daidzein intestinalderived metabolite equol. However, other products such as genistein, daidzein, glycitein and their respective β-glycosides of genistein and daidzein possess estrogenic activity [13]. Ellagitannins are metabolized to urolithin A and B which showed estrogenic activity [15, 22]. Also, lignans are metabolized in the gut to produce the most estrogenic enterolignans, enterodiol and enterolactone [18].

On the other hand, the chemical similarity between 17β-estradiol and phytoestrogens confers the capability to interact with estrogen receptors (ERs). They produce effects through genomic actions with ERs alpha and beta (α, β) or non-genomic actions via membrane G-protein receptors (GPER) such as GPR30 and mERα and mERβ [23]. These receptors differ in tissue distribution, ligand selectivity and transcriptional processes and, therefore, also differ in their physiological effects on its activation [24–26]. These interactions between phytoestrogens and ERs results on estrogenic and/or anti-estrogenic effects, so that phytoestrogens are considered as selective estrogen receptor modulators (SERMs) [27–29].

Several in vitro assays suggest that phytoestrogens, especially isoflavones, have a significant preference for ERβ rather than for ERα (8- to 40-fold) [30–33]. Some authors explain this preference through steric interaction and through the difference in the attractive potential of hydrogen bonds between the ERs and phytoestrogens, which is higher in ERβ [34]. It is thought, that in some way the beneficial actions of the estrogenic compounds are related to the ERβ, in part because the activation of ERβ has been associated with the anti-proliferative actions of phytoestrogens [35–37].

GPER activation by phytoestrogens has been relatedto cardiovascular, liver enzymatic and neuroprotective actions [35, 38–40]. Some research groups have proposed that the GPR30 also take part in the endocrine disrupting action of phytoestrogens [41]. Phytoestrogens also show high potency in non-genomic responses. Therefore, it is proposed that their binding affinities could be higher for mERs [42] albeit the involvement of these receptors in the phytoestrogens actions is less explored.

As it can be seen phytoestrogens also possess a complex mechanism of actions to exert their properties, for example, the rapid neuroprotective activity of resveratrol against cerebral ischemia is mediated by ERα and ERβ, and it is blocked by the estrogen receptor antagonist ICI 182 780 [36]. In contrast, Daidzein protects from excitotoxicity induced by glutamate via ERβ and GPR30 [35].

### **4. Alternative to the hormone replacement therapy on menopause**

### **4.1. Clinical studies**

of phytoestrogens. It is known that phytoestrogens are mostly as glycosides and that only the aglycone fraction is bio-available to produce biological effects [17]. Some phytoestrogens, such as isoflavones, ellagitannins and lignans, require the action of gut bacterial enzymes to produce equol, urolithins and enterolignans, respectively [16, 18, 19]. These subproducts have more bioavailability and have more estrogenic/anti-estrogenic and anti-oxidant, anti-inflammatory and anti-proliferative activity than their precursors [20]. Furthermore, it is proposed that the biotransformation of isoflavones, ellagitannins and lignans by intestinal microbiota is essential in protection against menopausal symptoms. Also against certain chronic diseases, such as cancer, cardiovascular disease and osteoporosis [15], suggesting that the main discrepancies between a successful treatment versus lack of effect could be

In this line, several reports indicate that coumestans—coumestrol and methoxycoumestrol show estrogenic activity; the most active compound of isoflavones is daidzein intestinalderived metabolite equol. However, other products such as genistein, daidzein, glycitein and their respective β-glycosides of genistein and daidzein possess estrogenic activity [13]. Ellagitannins are metabolized to urolithin A and B which showed estrogenic activity [15, 22]. Also, lignans are metabolized in the gut to produce the most estrogenic enterolignans, entero-

On the other hand, the chemical similarity between 17β-estradiol and phytoestrogens confers the capability to interact with estrogen receptors (ERs). They produce effects through genomic actions with ERs alpha and beta (α, β) or non-genomic actions via membrane G-protein receptors (GPER) such as GPR30 and mERα and mERβ [23]. These receptors differ in tissue distribution, ligand selectivity and transcriptional processes and, therefore, also differ in their physiological effects on its activation [24–26]. These interactions between phytoestrogens and ERs results on estrogenic and/or anti-estrogenic effects, so that phytoestrogens are considered

Several in vitro assays suggest that phytoestrogens, especially isoflavones, have a significant preference for ERβ rather than for ERα (8- to 40-fold) [30–33]. Some authors explain this preference through steric interaction and through the difference in the attractive potential of hydrogen bonds between the ERs and phytoestrogens, which is higher in ERβ [34]. It is thought, that in some way the beneficial actions of the estrogenic compounds are related to the ERβ, in part because the activation of ERβ has been associated with the anti-proliferative

GPER activation by phytoestrogens has been relatedto cardiovascular, liver enzymatic and neuroprotective actions [35, 38–40]. Some research groups have proposed that the GPR30 also take part in the endocrine disrupting action of phytoestrogens [41]. Phytoestrogens also show high potency in non-genomic responses. Therefore, it is proposed that their binding affinities could be higher for mERs [42] albeit the involvement of these receptors in the phytoestrogens

As it can be seen phytoestrogens also possess a complex mechanism of actions to exert their properties, for example, the rapid neuroprotective activity of resveratrol against cerebral ischemia

explained by the low bioavailability of phytoestrogens [21].

as selective estrogen receptor modulators (SERMs) [27–29].

diol and enterolactone [18].

86 A Multidisciplinary Look at Menopause

actions of phytoestrogens [35–37].

actions is less explored.

During menopause, symptoms such as body weight changes, vaginal dryness, hot flushes, sweating, sleep disturbances and loss of bone density may occur, also cognitive disturbance, mood changes and depression episodes that lead women to a poor quality of life [43]. Symptoms could vary in intensity and in some women, they could be debilitating, particularly for those women who have a previous experience of depression and anxiety in addition to vasomotor, insomnia, weight gain and stressful life events [44].

Hormone replacement therapy (HRT) is the first line of treatment followed by the treatment with selective serotonergic reuptake inhibitors antidepressants [2, 45]. Despite their benefits and efficacy for reducing most of the discomforts of menopausal women, the long-term use of HRT has been extremely controversial because of the adverse events associated. These include an increase in the risk of stroke and venous thromboembolism, an increase in endometrial, ovarian and breast cancer, in addition to the regular side effects of HRT such as headaches, weight changes, nausea and pruritus, among others. On the other hand, it has been reported that the adverse effects depend on several factors. Randomized trials have shown that the risk of presenting adverse effects is mainly given in women older than 60 years old, women during postmenopausal and after 5 years of the continued usage of the HRT.

Other therapies including non-pharmacological interventions have been recommended such as psychotherapy to address the psychological symptoms, acupuncture, physical exercise, nutritional interventions, botanical products and folk medicine, among others [44, 46].

Nevertheless, it is increasingly common for women to prefer an alternative therapy based on the intake of therapeutic compounds of natural origin instead. The alternative therapy can be based either on the consumption of food that may provide health benefits beyond nutrition (functional food) or on the administration of compounds isolated from food (nutraceuticals) with the same purpose. In this sense, phytochemicals as phytoestrogens have received much attention because of their particular health benefits which have allowed the emergence of an alternative to HRT.

Most of the therapies used to treat menopausal symptoms have been focusedon alleviating vasomotor and night sweat complaints. One of the most popular therapies is based in the use of black cohosh [33], Valerian and St John's wort [33, 46] due to the lack of estrogenic effects.

Briefly, black cohosh (*Cimicifuga racemosa L. Synonym Actearacemosa L*.) has been used for centuries by native Americans for a variety of women's health issues [33]. It is agreed that black cohosh is not estrogenic and its mechanism of action may involve modulation of the serotonergic system in a similar manner than antidepressants [1]. This botanical product has been tested in several trials given contradictory results. Indeed, the main effects appear to be related to vasomotor and emotional symptoms [33, 47]. For example, in a multicenter randomized, double-blind, placebo-controlled, parallel group trial, the effect of several doses of black cohosh was tested taking into consideration as a primary outcome the difference in menopausal symptoms (vasomotor, psychological and somatic), assessed by the Kupperman Menopausal Index between baseline and week 12. Secondary efficacy variables were patients' self-assessments of General Quality of Life (QoL), responder rates and safety. Compared to placebo, patients receiving black cohosh showed a significant reduction in the severity of vasomotor and psychological symptoms and improved general QoL in a dose-dependent manner from baseline to endpoint [47]. In contrast, recent clinical trials have reported adverse effects of black cohosh with no significant difference from placebo for relief of hot flashes or improving QoL in Thai women [48].

The phytoestrogens mostly used with documented effects are isoflavones. These compounds obtained from different sources have been used primarily to alleviate vasomotor symptoms, but the results appear not to be consistent on mood complaints. For example, in a metaanalysis (43 randomised controlled trials with 4364 participants) that evaluate the effect of isoflavones from soy and red clover in the treatment of hot flushes and insomnia associated with menopause, no significant difference overall was reported in the incidence of hot flushes between participants taking Promensil (a red clover extract that contains isoflavone biochanin A and formononetin) and those given placebo. In this review, four trials suggested that extracts with high levels (>30 mg/d) of genistein consistently reduced the frequency of hot flushes. Some of these trials found that phytoestrogen treatments alleviated the frequency and severity of hot flushes and night sweats when compared with placebo, but many trials were small and were determined to be at high risk of bias. A strong placebo effect was noted in most trials, with a reduction in frequency ranging from 1 to 59% with placebo. Discrepant results could be related to the amount of isoflavone in the active treatment arm, the severity of vasomotor symptoms or trial quality factors [49].

Other studies tested the effect of red clover and also found controversial results. For example, a trial of 72 women randomly divided between placebo and 40 mg dried red clover daily for 12 weeks showed a significant reduction in menopausal symptoms as measured by the Menopause Rating Scale [50]. In contrast, other clinical trials have not shown a significant difference from placebo, particularly for hot flashes relief [5]. Interestingly, red clover has proestrogens, biochannin A and formonetin, which are metabolized by CYP 450 in the gut and liver in genistein and daidzein [51], suggesting more bioavailability compared with soy products. This could be a reason why the use of red clover appears to be more effective than soy in the clinical trials [52].

Kudzu (*Pueraria lobata* Willd.) Ohwi (Fabaceae) is a traditional Chinese medicine for the treatment of the symptoms of menopause [1]; the major isoflavone in kudzu is puerarin, which is metabolized to daidzein by gut microbiota. Clinical trials with kudzu reported no significant changes in the menopausal complaints compared with control group [53].

Other compounds with estrogenic activity that differ from isoflavones have been tested, for example Hop (*Humulus lupulus* L.) (Cannabaceae). Hop extracts are in some dietary supplements used for managing menopausal symptoms [54]. The most potent phytoestrogen in hops is the ERα-selective agonist 8-prenylnaringenin (8-PN), which is 100-fold more potent than the ERβselective isoflavones genistein and daidzein [33]. Clinical trials suggest positive results of 8-PN in reducing the symptoms of menopause [54] however due to their high affinity to ERα; it is important to evaluate the safety on the endometrium and other hormone-sensitive tissues [33].

serotonergic system in a similar manner than antidepressants [1]. This botanical product has been tested in several trials given contradictory results. Indeed, the main effects appear to be related to vasomotor and emotional symptoms [33, 47]. For example, in a multicenter randomized, double-blind, placebo-controlled, parallel group trial, the effect of several doses of black cohosh was tested taking into consideration as a primary outcome the difference in menopausal symptoms (vasomotor, psychological and somatic), assessed by the Kupperman Menopausal Index between baseline and week 12. Secondary efficacy variables were patients' self-assessments of General Quality of Life (QoL), responder rates and safety. Compared to placebo, patients receiving black cohosh showed a significant reduction in the severity of vasomotor and psychological symptoms and improved general QoL in a dose-dependent manner from baseline to endpoint [47]. In contrast, recent clinical trials have reported adverse effects of black cohosh with no significant difference from placebo for relief of hot flashes or

The phytoestrogens mostly used with documented effects are isoflavones. These compounds obtained from different sources have been used primarily to alleviate vasomotor symptoms, but the results appear not to be consistent on mood complaints. For example, in a metaanalysis (43 randomised controlled trials with 4364 participants) that evaluate the effect of isoflavones from soy and red clover in the treatment of hot flushes and insomnia associated with menopause, no significant difference overall was reported in the incidence of hot flushes between participants taking Promensil (a red clover extract that contains isoflavone biochanin A and formononetin) and those given placebo. In this review, four trials suggested that extracts with high levels (>30 mg/d) of genistein consistently reduced the frequency of hot flushes. Some of these trials found that phytoestrogen treatments alleviated the frequency and severity of hot flushes and night sweats when compared with placebo, but many trials were small and were determined to be at high risk of bias. A strong placebo effect was noted in most trials, with a reduction in frequency ranging from 1 to 59% with placebo. Discrepant results could be related to the amount of isoflavone in the active treatment arm, the severity of vasomotor symptoms

Other studies tested the effect of red clover and also found controversial results. For example, a trial of 72 women randomly divided between placebo and 40 mg dried red clover daily for 12 weeks showed a significant reduction in menopausal symptoms as measured by the Menopause Rating Scale [50]. In contrast, other clinical trials have not shown a significant difference from placebo, particularly for hot flashes relief [5]. Interestingly, red clover has proestrogens, biochannin A and formonetin, which are metabolized by CYP 450 in the gut and liver in genistein and daidzein [51], suggesting more bioavailability compared with soy products. This could be a reason why the use of red clover appears to be more effective than soy in the clinical trials [52]. Kudzu (*Pueraria lobata* Willd.) Ohwi (Fabaceae) is a traditional Chinese medicine for the treatment of the symptoms of menopause [1]; the major isoflavone in kudzu is puerarin, which is metabolized to daidzein by gut microbiota. Clinical trials with kudzu reported no significant

Other compounds with estrogenic activity that differ from isoflavones have been tested, for example Hop (*Humulus lupulus* L.) (Cannabaceae). Hop extracts are in some dietary supplements

changes in the menopausal complaints compared with control group [53].

improving QoL in Thai women [48].

88 A Multidisciplinary Look at Menopause

or trial quality factors [49].

Rhubard (*Rheum rhaponticum* L.) (Polygonaceae). Rhubard is a plant used for menopausal symptoms relief in Germany [54]. The extract from roots of rhubard mainly consists of rhaponticin and desoxyrhaponticin, which are converted to the resveratrol-like aglycones rhapontigenin and desoxyrhapontigenin by the microbiome. Rhapontigenin is more active than desoxyrhapontigenin, and it is suggested that P450-catalyzed O-demethylation giving the resveratrol-catechol piceatannol might be responsible for its estrogenic activity [14, 55]. Clinical trials show that the rhubarb extract was effective and successfully decreased the Menopause Rating Scale and increased QoL [56–58].

Flaxseed (*Linum usitatissimum* L.) (Linaceae). Flaxseed is a primary source of lignans that are metabolized by the microbiota into the phytoestrogens, enterolactone and enterodiol [18]. In a randomized placebo-controlled clinical trial (90 women, 1 g/day flaxseed extract), modest but significant effects were observed in self-reporting relief of menopausal symptoms [59]. Nevertheless, a meta-analysis that included randomized clinical trials examining the efficacy of flaxseed for menopausal symptoms, concluded that there is little evidence to support the use of this dietary supplement for menopause or bone health [60].

Another product most employed in South America is maca (*Lepidium meyenii* Walp.) (Brassicaceae), it is used for hormonal balance, especially for menopausal symptoms [54]. Albeit the active phytoestrogen has not been detected, the extract of maca showed estrogenic effect increasing proliferation in MCF-7 cells. A systematic review of clinical trials concluded that evidence of the effectiveness of maca for the relief of menopausal symptoms was limited. However, because of the sample size, the number of trials and the quality of the trials, it is not pertinent to establish definite conclusions about the efficacy and safety [61].

Recently, in a placebo-controlled trial, the efficacy of resveratrol and equol supplementation was tested on menopausal women aged 50–55 years who received 200 mg of fermented soy containing 10 mg of equol and 25 mg of resveratrol (1 tablet/day) during 12 weeks. The primary outcome was the change in score on the Menopause Rating Scale, used to evaluate the severity of age-/menopause-related complaints. Additional outcomes included the Hamilton Rating Scale for Depression (HAM-D) and Nottingham Health Profile (NHP), which were used specifically to assess sleep quality. Treatment was effective to reduce Menopause Rating Scale and HAM-D scores, importantly on work and activity items and with a slight effect on anxiety-related items [62].

According to the results of meta-analyses, there is no enough clinical evidence that supports the use of phytoestrogens as HRT to alleviate all symptoms of menopause. Albeit an improvement in the quality of life is reported. An important issue to consider is the use of standardized phytoestrogens and ethnicity of the women included in the studies since these factors could be crucial to obtain a positive result for those phytoestrogens that require specific microbiota biotransformation. Promising results are derived from isoflavones and their precursor because of non-adverse effects reported. However, in all cases, more controlled-clinical trials using large samples with women of different ethnicities are required.

### **4.2. Preclinical studies**

In contrast to the clinical studies where the phytoestrogens were evaluated mainly to prevent or alleviate the vasomotor symptoms, in preclinical data, studies were focused on the evaluation of anxious and depressive-like behaviors. Some of the phytoestrogens are considered selective estrogens receptors modulators and are derived from the metabolism of isoflavones. Importantly, most of them showed an affinity for ERβ, characteristic that may explain their effect partially as an antidepressant [63]. However, others showed an affinity for ERα or membrane receptors, making the study of their mechanism of action complex.

Early studies evaluated the effect of dietary phytoestrogens as anxiolytic-like agents [64]. The authors tested the effect of phytoestrogens in the offspring of mothers fed with a dietary soy derived phytoestrogens (600 µg/g) and found a reduction in the anxiety behavior in those animals that were maintained with soy diet when adulthood. Rodents fed with soy also showed less body weight [64]. Unfortunately, in this paper, the authors did not indicate the phytoestrogens bounded with the behavioral effect but reported high levels of equol in plasma, the more active metabolite of isoflavones found in the soy [14].

After that, several doses of a diet rich in phytoestrogens (200 or 600 ppm of phytoestrogens in diet) and equol injections (5 mg/kg) were evaluated in the forced swimming test in rats under different endocrine conditions: intact, ovariectomized and aged rats with natural ovarian failure [65]. Interestingly, the latter group resembles an animal model of "natural menopause" because rats are acyclic, and it is the only report, as far as we know, that evaluate the effect of the isoflavones under this condition. Authors showed that soy diet rich in phytoestrogens and equol produced antidepressant-like effects at the same time that induces a reduction of body weight and white adipose tissue in all endocrine conditions. After the soy-rich diet, high plasmatic levels of genistein, daidzein and equol were detected in those animals that received the highest dose [65]. Unfortunately, the authors did not evaluate anxiety-like behaviors.

In contrast, no effect or anxiogenic effect was reported after a rich isoflavone diet administration [66, 67]. It is important to mention that these data were generated in male rats instead of female rats where more information is needed. Briefly, when a soy-rich diet containing 150 µg/g total isoflavones (daidzein and genistein) was dispensed to young male Lister rats, an anxiogenic effect was reported in the elevated plus-maze and social interaction test. Diet neither affected water intake nor the weight of rats but enhanced the corticosterone and vasopressin stress-response [66], suggesting an increase in sensitivity to stress. The authors explained the apparent discrepancy between results, i.e. Lund and Lephard [64] versus Hartley et al. [66] considering timing and dose used (150 µg/g versus 600 µg/g). Other difference that could be noted is the strain of rats, Long-Evans [64] versus Lister rats [66] and the sex of the rats. The latter is an important issue since Harley et al. [66] used intact male rats, and Lund and Lephard [64] used intact male and female rats finding positive results in anxiety in females but impaired the anxious-like state in males. Further, Patisaul et al. [67] showed that the administration of a soy-rich (600 µg/g) diet to gonadally intact male rats produced anxiogenic effects. Furthermore, authors tested high (20 mg/kg) and low (3 mg/ kg) doses of equol and resveratrol (3 and 20 mg/kg) in two animal models of anxiety in intact male rats. The authors reported that these compounds did not produce any effect after 3 days of treatment and discussed the possibility that the endocrine condition that prevails in males could be a factor to explain the lack of effect [67].

biotransformation. Promising results are derived from isoflavones and their precursor because of non-adverse effects reported. However, in all cases, more controlled-clinical trials

In contrast to the clinical studies where the phytoestrogens were evaluated mainly to prevent or alleviate the vasomotor symptoms, in preclinical data, studies were focused on the evaluation of anxious and depressive-like behaviors. Some of the phytoestrogens are considered selective estrogens receptors modulators and are derived from the metabolism of isoflavones. Importantly, most of them showed an affinity for ERβ, characteristic that may explain their effect partially as an antidepressant [63]. However, others showed an affinity for ERα or mem-

Early studies evaluated the effect of dietary phytoestrogens as anxiolytic-like agents [64]. The authors tested the effect of phytoestrogens in the offspring of mothers fed with a dietary soy derived phytoestrogens (600 µg/g) and found a reduction in the anxiety behavior in those animals that were maintained with soy diet when adulthood. Rodents fed with soy also showed less body weight [64]. Unfortunately, in this paper, the authors did not indicate the phytoestrogens bounded with the behavioral effect but reported high levels of equol in plasma, the

After that, several doses of a diet rich in phytoestrogens (200 or 600 ppm of phytoestrogens in diet) and equol injections (5 mg/kg) were evaluated in the forced swimming test in rats under different endocrine conditions: intact, ovariectomized and aged rats with natural ovarian failure [65]. Interestingly, the latter group resembles an animal model of "natural menopause" because rats are acyclic, and it is the only report, as far as we know, that evaluate the effect of the isoflavones under this condition. Authors showed that soy diet rich in phytoestrogens and equol produced antidepressant-like effects at the same time that induces a reduction of body weight and white adipose tissue in all endocrine conditions. After the soy-rich diet, high plasmatic levels of genistein, daidzein and equol were detected in those animals that received the

highest dose [65]. Unfortunately, the authors did not evaluate anxiety-like behaviors.

In contrast, no effect or anxiogenic effect was reported after a rich isoflavone diet administration [66, 67]. It is important to mention that these data were generated in male rats instead of female rats where more information is needed. Briefly, when a soy-rich diet containing 150 µg/g total isoflavones (daidzein and genistein) was dispensed to young male Lister rats, an anxiogenic effect was reported in the elevated plus-maze and social interaction test. Diet neither affected water intake nor the weight of rats but enhanced the corticosterone and vasopressin stress-response [66], suggesting an increase in sensitivity to stress. The authors explained the apparent discrepancy between results, i.e. Lund and Lephard [64] versus Hartley et al. [66] considering timing and dose used (150 µg/g versus 600 µg/g). Other difference that could be noted is the strain of rats, Long-Evans [64] versus Lister rats [66] and the sex of the rats. The latter is an important issue since Harley et al. [66] used intact male rats, and Lund and Lephard [64] used intact male and female rats finding positive results in anxiety in females but impaired the anxious-like state in males. Further, Patisaul et al. [67]

using large samples with women of different ethnicities are required.

brane receptors, making the study of their mechanism of action complex.

more active metabolite of isoflavones found in the soy [14].

**4.2. Preclinical studies**

90 A Multidisciplinary Look at Menopause

Following this idea, recently it was hypothesized that the role of isoflavones in the regulation of anxiety and depressive-like behavior depends on the endocrine status [68]. To test this hypothesis, the authors evaluated the anxiolytic- and antidepressant-like effect of isoflavonerich diet (199.4 µg/g) in ovariectomized rats exposed, or not exposed, to estradiol replacement. Data showed that anxiolytic and antidepressant-like effects depend on the endocrine state that prevails during the treatment with isoflavones. In this case, an isoflavone diet combined with estradiol restitution promotes anxiety; in contrast, the same combination promoted an antidepressant-like effect [68]. Unfortunately, authors did not show evidence about the phytoestrogens that could be responsible for the observed effect.

The isoflavone genistein has been evaluated as an antidepressant and anxiolytic compound. This phytoestrogen also showed more affinity for ERβ than ERα [69], and recent reports also suggested that it binds to ERm. Rodríguez-Landa et al. [70]) assayed several doses of this compound (0.25, 0.5 and 1.0 mg/kg, i.p.) after 4 days of administration in Wistar rats with 12-weeks after the elimination of ovaries. This model resembled a long-term period of menopause and was used to evaluate if genistein was able to induce anxiolytic-like effects as hormone replacement therapy after a long-term ovariectomy. In this study, authors showed that genistein was effective in reducing anxiety-like behavior in the black and white model after a long-term postovariectomy. Interestingly, it has been reported that E2 is ineffective to produce behavioral effects after a long-term ovaries removal [71–73]. Therefore, the results obtained with genistein open the opportunity to use this compound as a restitution therapy. Furthermore, clinical and preclinical studies reported that genistein lacks stimulatory effects in breast and uterus [33]. Genistein also showed antidepressant-like effects in rats subjected to the forced swimming test. In this case, genistein (10 mg/kg) was administered during 14 days to ovariectomized rats and reduction of immobility behavior was observed. Data also indicated that genistein increased dopamine and restored the serotonin levels in the hippocampus at a dose of 10 mg/kg [74]. Interestingly, the effect of this compound was also tested after a subacute administration (i.e., three injections in 24 hours) and no effect was observed. This result suggested a genomic mechanism of action [74].

Another compound with estrogenic properties that has been tested is coumestrol (7,12-dihydrocoumenstan), which is considered a SERM that shows an affinity for the ERβ [69]. This compound was assayed in the forced swimming test and several models of anxiety after systemic (10 µg/kg) and intracerebral administrations (2 µg/µl/slide) to ovariectomized rats. A reduction of depressive-like and anxiety-like behavior was reported after both routes of administration [63]. As it can be noted, coumestrol is effective as an anxiolytic or antidepressant compound in ovariectomized rats; however, it is necessary to evaluate its effect in young intact and acyclic female rats to establish whether the effect of this compound remains even in the presence of ovarian secretion.

Also, secoisolariciresinol (SECO) is a lignan type phytoestrogen mainly found in flaxseed that can be metabolized to enterodiol and enterolactone. This compound was administered (5, 10 and 20 mg/kg, intragastric) during 14 days to ovariectomized mice and tested in two animal models for the screening of antidepressant drugs, the tail suspension test and the forced swimming test. The authors reported an antidepressant-like effect of SECO in both behavioral tests. Furthermore, this compound restored noradrenaline brain levels and increased dopamine and serotonin concentrations without promoting a stimulatory effect on the uterus [75]. An important difference in comparison to other protocols presented here is that SECO was administered immediately after the ovariectomy. Therefore, the restitution started before a real drop in endogenous estrogen levels, suggesting a model of perimenopause rather than a menopause model.

Phytoestrogens appear to promote anxiolytic and antidepressant-like actions in animal models. However, it can be noted that the time, the dose and endocrine state are factors that may condition the effect of these estrogenic compounds. In general, acute interventions are ineffective; most of the reports indicate that more than 3 days are necessary to observe an anxiolytic or antidepressant-like effect. For isoflavones, their effect appears to depend on the time of restitution and the endocrine state of rats. In this line, the fact that their anxiolytic-like effect is observed in ovariectomized or acyclic females but not in intact rats suggests that isoflavones are working as a restitution therapy and the levels of phytoestrogens that are bioavailable after diet administration are enough to induce changes in the respective receptors like a natural estrogen.

### **5. Alternative sources of phytoestrogens**

### **5.1.** *Punica granatum* **L. (Lythraceae)**

Pomegranate is a fruit native of Western Asia and North Africa. However, it is now cultivated in most of the Mediterranean and North America region [76]. **Table 1** shows the main phytochemicals reported for pomegranate.

Over the last decades, pomegranate and pomegranate extracts have demonstrated to possess several beneficial health effects for which it is considered a functional food. Clinical and preclinical studies have shown that pomegranate has anti-oxidant [77], anti-inflammatory, antitumorigenic, anti-microbial [78], anti-obesity [79], anti-nociceptive [80], neuroprotective [81] and antidepressant-like properties [82–84]. Interestingly, most of the health benefits of pomegranate are attributed to its high content of polyphenols, which represents the 26–30% of the total weight of the fruit [85]. The main polyphenols present in the pomegranate are ellagitannins, such as punicalagin (α and β), and flavonoids such as anthocyanidins, catechins, flavonols and isoflavones [80, 86–88]. Ellagitannins are a type of hydrolyzable tannins with several hexahydroxydiphenoyl (HHDP) groups esterified to sugar moieties. When consumed, ellagitannins are easily hydrolyzed to ellagic acid in the acidic conditions of the gastric juice because of its hydrophilic nature. Therefore, on different portions of the small and large intestine, ellagitannins are transformed by bacterial metabolism to dibenzopyranone compounds called urolithins. These compounds have recently demonstrated to possess estrogenic activity on *in-vitro* assays; this particularity makes pomegranate an excellent source of phytoestrogens [16, 22, 78, 89]. Under this premise, some Use of Phytoestrogens for the Treatment of Psychiatric Symptoms Associated with Menopause ... http://dx.doi.org/10.5772/intechopen.69541 93

**Table 1.** Phytochemicals found in *Punica granatum* L.

Also, secoisolariciresinol (SECO) is a lignan type phytoestrogen mainly found in flaxseed that can be metabolized to enterodiol and enterolactone. This compound was administered (5, 10 and 20 mg/kg, intragastric) during 14 days to ovariectomized mice and tested in two animal models for the screening of antidepressant drugs, the tail suspension test and the forced swimming test. The authors reported an antidepressant-like effect of SECO in both behavioral tests. Furthermore, this compound restored noradrenaline brain levels and increased dopamine and serotonin concentrations without promoting a stimulatory effect on the uterus [75]. An important difference in comparison to other protocols presented here is that SECO was administered immediately after the ovariectomy. Therefore, the restitution started before a real drop in endogenous estrogen levels, suggesting a model of perimenopause rather than a menopause model. Phytoestrogens appear to promote anxiolytic and antidepressant-like actions in animal models. However, it can be noted that the time, the dose and endocrine state are factors that may condition the effect of these estrogenic compounds. In general, acute interventions are ineffective; most of the reports indicate that more than 3 days are necessary to observe an anxiolytic or antidepressant-like effect. For isoflavones, their effect appears to depend on the time of restitution and the endocrine state of rats. In this line, the fact that their anxiolytic-like effect is observed in ovariectomized or acyclic females but not in intact rats suggests that isoflavones are working as a restitution therapy and the levels of phytoestrogens that are bioavailable after diet administration are enough to induce changes in the respective receptors like a natural estrogen.

Pomegranate is a fruit native of Western Asia and North Africa. However, it is now cultivated in most of the Mediterranean and North America region [76]. **Table 1** shows the main phyto-

Over the last decades, pomegranate and pomegranate extracts have demonstrated to possess several beneficial health effects for which it is considered a functional food. Clinical and preclinical studies have shown that pomegranate has anti-oxidant [77], anti-inflammatory, antitumorigenic, anti-microbial [78], anti-obesity [79], anti-nociceptive [80], neuroprotective [81] and antidepressant-like properties [82–84]. Interestingly, most of the health benefits of pomegranate are attributed to its high content of polyphenols, which represents the 26–30% of the total weight of the fruit [85]. The main polyphenols present in the pomegranate are ellagitannins, such as punicalagin (α and β), and flavonoids such as anthocyanidins, catechins, flavonols and isoflavones [80, 86–88]. Ellagitannins are a type of hydrolyzable tannins with several hexahydroxydiphenoyl (HHDP) groups esterified to sugar moieties. When consumed, ellagitannins are easily hydrolyzed to ellagic acid in the acidic conditions of the gastric juice because of its hydrophilic nature. Therefore, on different portions of the small and large intestine, ellagitannins are transformed by bacterial metabolism to dibenzopyranone compounds called urolithins. These compounds have recently demonstrated to possess estrogenic activity on *in-vitro* assays; this particularity makes pomegranate an excellent source of phytoestrogens [16, 22, 78, 89]. Under this premise, some

**5. Alternative sources of phytoestrogens**

**5.1.** *Punica granatum* **L. (Lythraceae)**

92 A Multidisciplinary Look at Menopause

chemicals reported for pomegranate.

research groups have sought its therapeutic potential for the treatment of symptoms in menopause. In 2012, the therapeutic effect of a 12-week schedule of pomegranate seed oil (PGS) on menopausal symptoms was investigated with a neutral response, i.e., PGS reduced menopausal symptoms, but with no significance, authors remarked the importance of evaluating the PGS for a longer period [90]. Furthermore, a systematic review reported the effect of pomegranate juice in osteoporosis, osteoarthritis, or rheumatoid arthritis. All the studies reported positive effects of pomegranate extract or juice on osteoporosis, osteoarthritis and rheumatoid arthritis [91].

Preclinical studies have reported that the juice of pomegranate reduced menopausal symptoms in animal models by inducing antidepressant-like effects and decreasing bone loss [92]. In our laboratory, an extract of pomegranate in the elevated plus-maze for the screening of anxiolytic action and the forced swimming test for an antidepressant-like effect (unpublished results) was evaluated. This extract has a high content of ellagitannins and previously showed anti-inflammatory and antinociceptive properties [80] After 7 days of intraperitoneal administration, a reduction of anxiety-like behavior was detected and a lack of effect in the forced swimming test. The decrease of anxiety was detected at 1.0 mg/kg (see **Figure 4**). Importantly,

**Figure 4.** Effect of several doses (0.1, 1.0, 10 mg/kg, i.p) of aqueous extract of pomegranate (*Punica granatum* L.) in the elevated plus-maze (A) and the forced swimming test (panel B) after 7 days of treatment. Pomegranate extract reduced the anxiety-like behavior (panel A) but lacks antidepressant-like effect (B). Data are presented as mean ± SE of 10–12 ovariectomized rats per group. \**p* < 0.05 versus control group; <sup>+</sup> *p* < 0.05 versus 0.1 mg/kg, One-way-ANOVA followed by Student-Newman Keuls test. Unpublished results.

the fact that the administration route was intraperitoneal suggests that other phytochemicals more than ellagitannins, which require of microbiota transformation, could be present in the extract. Future experiments may contribute to elucidate the phytochemical bounded in the anxiolytic effect of pomegranate.

### **5.2.** *Brassica oleraceae* **var.** *italica*

In our laboratory, an extract of pomegranate in the elevated plus-maze for the screening of anxiolytic action and the forced swimming test for an antidepressant-like effect (unpublished results) was evaluated. This extract has a high content of ellagitannins and previously showed anti-inflammatory and antinociceptive properties [80] After 7 days of intraperitoneal administration, a reduction of anxiety-like behavior was detected and a lack of effect in the forced swimming test. The decrease of anxiety was detected at 1.0 mg/kg (see **Figure 4**). Importantly,

**Figure 4.** Effect of several doses (0.1, 1.0, 10 mg/kg, i.p) of aqueous extract of pomegranate (*Punica granatum* L.) in the elevated plus-maze (A) and the forced swimming test (panel B) after 7 days of treatment. Pomegranate extract reduced the anxiety-like behavior (panel A) but lacks antidepressant-like effect (B). Data are presented as mean ± SE of 10–12

*p* < 0.05 versus 0.1 mg/kg, One-way-ANOVA followed by

ovariectomized rats per group. \**p* < 0.05 versus control group; <sup>+</sup>

Student-Newman Keuls test. Unpublished results.

94 A Multidisciplinary Look at Menopause

Broccoli (*Brassica oleracea* var. *italica* Plenck) belongs to the Brassicaceae of cruciferous family where cabbage, brussels sprouts and radish can also be found [93]. It is native to the Anatolian peninsula and now is widely cultivated in other parts of the world. The phytochemical content of broccoli is shown in **Table 2**. As it can be seen, broccoli is also a source of important polyphenols, and consequently, phytoestrogens since in its composition, it can be detected quercetin, kaempferol, daidzein, antocyanins [93, 94], coumestans and lignans [45, 95].

**Table 2.** Phytochemicals in different parts of *Brassica oleraceae*.

Broccoli is also a source of a potent anti-oxidant and anti-inflammatory compound called sulforaphane (1-isothiocyanato-4-methylsulfinylbutane) which is an organosulfur compound [118]. Several reports indicated that this compound might prevent depressive-like behavior induced by the inflammatory process. For example, acute sulforaphane at 3–30 mg/kg and glucorophanin (glucosinolate precursor of sulforaphane) in the diet were tested in male C57BL/6 mice. In this case, it was to determine whether these compounds were able to prevent the onset of depression-like behavior after an induction of inflammation by lipopolysaccharide administration [118]. In this chapter, authors also evaluate the effect of sulforaphane on brain-derived neurotrophic factor (BDNF) levels, synaptogenesis protein and dendritic spine density in the brain. The results showed that sulforaphane prevents the increase of TNF-α, IL-10 and microglia activation blocking the inflammation process at the same time that decreased the depressive-like behavior evaluated by two behavioral test. Interestingly, sulforaphane also reverses the reduction of BDNF expression and dendritic spines induced by inflammation process [118].

In another study, the effect of sulporaphane and glucorophaninwas tested on depressive-like behavior after repeated social defeat stress using Nrf2 knock-out mice. Nrf2 is a transcription factor keap-1 system that plays a role in the inflammation and evidence has shown that both peripheral and central inflammation plays a crucial role in the pathophysiology of depression [119]. The administration of diet rich in sulforaphane and glucorophanin prevented the depressive-like behavior during adulthood; further authors showed that dietary intake of SFN-rich food during juvenile stages and adolescence could confer stress resilience in adulthood [119].

Contrasting results have also been reported, for example, Balb/c mice received sulforaphane (50 mg/kg) previous to the injection of lipopolysaccharide afterward sickness behavior (an animal model of depression), and the proinflammatory response was evaluated in the hippocampus. The authors reported that sulforaphane administration prevented the induction of pro-inflammatory mediators (IL-b; IL-6, Cybb, INOS) but did not improve sickness behavior [120, 121]. Therefore, the use of sulforaphane to prevent depression-like behavior is inconclusive.

As far as we know, there is no information about the use of sulforaphane or glucorophanin in animal models of menopause. However, it has been suggested that the advantage of broccoli consumption is that some phytochemicals promote the conversion of 16-a-hydroxyestrone to 2-hydroxyestrone, the first is a carcinogenic metabolite that has been linked to breast cancer risk whereas the latter product does not exhibit estrogenic properties in breast tissue. Apparently, the ingestion of broccoli sprouts could be a good strategy for the treatment of menopause symptoms [2, 122, 123].

In our laboratory, several doses (0.1, 1.0, 10 mg/kg, i.p) of an extract of broccoli were evaluated for its anxiolytic and antidepressant-like effects after 7 days of administration to 3-week postovariectomized rats. The results indicated an anxiolytic—but not antidepressant-like effect (**Figure 5**, unpublished results). The phytochemical involved in this action is unknown and studies to reveal it are running.

The fact that sulforaphane exerts anti-inflammatory properties and that according to the aetiology of depression, the inflammatory process plays a major role in its aetiology, the consumption of food or nutraceuticals with sulforaphane could be suitable.

Use of Phytoestrogens for the Treatment of Psychiatric Symptoms Associated with Menopause ... http://dx.doi.org/10.5772/intechopen.69541 97

Broccoli is also a source of a potent anti-oxidant and anti-inflammatory compound called sulforaphane (1-isothiocyanato-4-methylsulfinylbutane) which is an organosulfur compound [118]. Several reports indicated that this compound might prevent depressive-like behavior induced by the inflammatory process. For example, acute sulforaphane at 3–30 mg/kg and glucorophanin (glucosinolate precursor of sulforaphane) in the diet were tested in male C57BL/6 mice. In this case, it was to determine whether these compounds were able to prevent the onset of depression-like behavior after an induction of inflammation by lipopolysaccharide administration [118]. In this chapter, authors also evaluate the effect of sulforaphane on brain-derived neurotrophic factor (BDNF) levels, synaptogenesis protein and dendritic spine density in the brain. The results showed that sulforaphane prevents the increase of TNF-α, IL-10 and microglia activation blocking the inflammation process at the same time that decreased the depressive-like behavior evaluated by two behavioral test. Interestingly, sulforaphane also reverses the reduction of BDNF expression and dendritic spines induced by inflammation process [118].

In another study, the effect of sulporaphane and glucorophaninwas tested on depressive-like behavior after repeated social defeat stress using Nrf2 knock-out mice. Nrf2 is a transcription factor keap-1 system that plays a role in the inflammation and evidence has shown that both peripheral and central inflammation plays a crucial role in the pathophysiology of depression [119]. The administration of diet rich in sulforaphane and glucorophanin prevented the depressive-like behavior during adulthood; further authors showed that dietary intake of SFN-rich food during juvenile stages and adolescence could confer stress resilience in adulthood [119].

Contrasting results have also been reported, for example, Balb/c mice received sulforaphane (50 mg/kg) previous to the injection of lipopolysaccharide afterward sickness behavior (an animal model of depression), and the proinflammatory response was evaluated in the hippocampus. The authors reported that sulforaphane administration prevented the induction of pro-inflammatory mediators (IL-b; IL-6, Cybb, INOS) but did not improve sickness behavior [120, 121].

As far as we know, there is no information about the use of sulforaphane or glucorophanin in animal models of menopause. However, it has been suggested that the advantage of broccoli consumption is that some phytochemicals promote the conversion of 16-a-hydroxyestrone to 2-hydroxyestrone, the first is a carcinogenic metabolite that has been linked to breast cancer risk whereas the latter product does not exhibit estrogenic properties in breast tissue. Apparently, the ingestion of broccoli sprouts could be a good strategy for the treatment of

In our laboratory, several doses (0.1, 1.0, 10 mg/kg, i.p) of an extract of broccoli were evaluated for its anxiolytic and antidepressant-like effects after 7 days of administration to 3-week postovariectomized rats. The results indicated an anxiolytic—but not antidepressant-like effect (**Figure 5**, unpublished results). The phytochemical involved in this action is unknown and

The fact that sulforaphane exerts anti-inflammatory properties and that according to the aetiology of depression, the inflammatory process plays a major role in its aetiology, the con-

sumption of food or nutraceuticals with sulforaphane could be suitable.

Therefore, the use of sulforaphane to prevent depression-like behavior is inconclusive.

menopause symptoms [2, 122, 123].

96 A Multidisciplinary Look at Menopause

studies to reveal it are running.

**Figure 5.** Effect of several doses (0.1, 1.0, 10 and 100 mg/kg, i.p) of aqueous extract of broccoli (*Brassica oleraceae* L) in the elevated plus-maze (A) and the forced swimming test (B) after 7 days of treatment. Broccoli extract reduced the anxietylike behavior (A) but lacks antidepressant-like effect (B). Data are presented as mean ± SE of 10–12 ovariectomized rats per group. \**p* < 0.05 versus control group; +*p* < 0.05 versus 0.1 mg/kg, One way-ANOVA followed by Student-Newman Keuls test. Unpublished results.

### **6. Comorbidity in menopause and alternative medicine**

Fibromyalgia (FM) is a chronic, generalized pain syndrome that affects the musculoskeletal system [124]. It is characterized not only by a widespread pain observed due to the presence of multiple tender points but also by depressive behavior, fatigue and sleep disturbances without any structural or inflammatory cause [125, 126]. Studies have consistently demonstrated a female predominance of this disease [127] with a major frequency in pre- and postmenopause condition supporting that an abrupt decline or a reduced time of exposure to ovarian hormones may contribute to FM [128].

Although FM is not an inflammatory disease, it is known that a neuroinflammation process can occur, which is described as an increase in the production of interleukins at the central nervous system level, such as IL-1β, IL-6, IL-8, IL-10 and TNF-α, and not at the peripheral level [129]. To date, it has not been possible to establish whether their elevated levels are associated with the painful process in FM since these have also been observed in patients with depression and sleep disorders [130]. The neuroendocrine alterations observed are usually at the level of the hypothalamic-pituitary-adrenal axis where there is hyperactivation, and it has been related to deficient levels of hormones [131] that could be part of the reasons of a major frequency in menopause [128].

As it was mentioned, anthocyanidins belong to the flavonoid group of plant-derived chemicals, which have been commonly used for the treatment of chronic diseases. One randomized clinic test was done to evaluate the efficacy of this compounds (40, 80 and 120 mg/day) in the treatment of FM compared with a placebo group. The evaluation had duration of 52 weeks with each treatment given for 12 weeks, preceded by a 4-week baseline period. Authors conclude that anthocyanidins showed small but significant benefits at a dosage of 80 mg/day in the treatment of primary FM, mainly in the sleep disturbance in the presence of minor adverse effects like indigestion or nausea [132].

Chronic fatigue syndrome is also comorbid linked to early menopause and FM since it involves the muscular, nervous, hormonal and immune systems; it is often misdiagnosed as depression [133]. Isoflavones (daidzein and genistein) were capable of reversing alterations like chronic fatigue syndrome in an experimental model in mice suggesting their protective effect in this neuroimmune-endocrine disease [134].

### **7. Concluding remarks**

### **Author details**

nervous system level, such as IL-1β, IL-6, IL-8, IL-10 and TNF-α, and not at the peripheral level [129]. To date, it has not been possible to establish whether their elevated levels are associated with the painful process in FM since these have also been observed in patients with depression and sleep disorders [130]. The neuroendocrine alterations observed are usually at the level of the hypothalamic-pituitary-adrenal axis where there is hyperactivation, and it has been related to deficient levels of hormones [131] that could be part of the reasons of a major

As it was mentioned, anthocyanidins belong to the flavonoid group of plant-derived chemicals, which have been commonly used for the treatment of chronic diseases. One randomized clinic test was done to evaluate the efficacy of this compounds (40, 80 and 120 mg/day) in the treatment of FM compared with a placebo group. The evaluation had duration of 52 weeks with each treatment given for 12 weeks, preceded by a 4-week baseline period. Authors conclude that anthocyanidins showed small but significant benefits at a dosage of 80 mg/day in the treatment of primary FM, mainly in the sleep disturbance in the presence of minor adverse

Chronic fatigue syndrome is also comorbid linked to early menopause and FM since it involves the muscular, nervous, hormonal and immune systems; it is often misdiagnosed as depression [133]. Isoflavones (daidzein and genistein) were capable of reversing alterations like chronic fatigue syndrome in an experimental model in mice suggesting their protective

**1.** Clinical reports show inconsistent results about the use of phytoestrogens effectiveness to treat vasomotor and psychiatric disorders associated with menopause. The biotransformation by microbiota to deliver the main active compounds appears to be fundamental to

**2.** Preclinical data show that the effect of phytoestrogens depends on the time of administration as well as the endocrine state of rats, suggesting that these factors could also contrib-

**3.** More studies are necessary to evaluate if the same phytoestrogen can induce both anxiolytic- and antidepressant-like action and if their effect depends on the endocrine state. **4.** Clinical and preclinical studies indicated that the use of phytoestrogens is safe due to the high antioxidant activity. However, meta-analysis studies are inconclusive. Therefore,

**5.** Functional food and nutraceuticals are an important source of a wide variety of phytoestrogens.

ute to explain the inconsistency between results observed in humans.

phytoestrogens as restitution therapy should be monitored.

frequency in menopause [128].

98 A Multidisciplinary Look at Menopause

effects like indigestion or nausea [132].

**7. Concluding remarks**

observe positive effects.

effect in this neuroimmune-endocrine disease [134].

Erika Estrada-Camarena<sup>1</sup> \*, Carolina López-Rubalcava2 , Brenda Valdés-Sustaita2 , Gabriel Sinhue Azpilcueta-Morales1 and Eva María González-Trujano<sup>3</sup>

\*Address all correspondence to<EMAIL_ADDRESS>
1 Laboratory of Neuropsychopharmacology, Neuroscience Division, National Institute of Psychiatry "Ramón de la Fuente", Mexico, Mexico

2 Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPN, Mexico, Mexico

3 Laboratory of Neuropharmacology of Natural Products, Neuroscience Division. National Institute of Psychiatry "Ramón de la Fuente", Mexico, Mexico

### **References**

estrogenic and antiestrogenic activities. Journal of Agricultural and Food Chemistry. 2006;**54**:1611-1620

[23] Watson CS, Bulayeva NN, Wozniak AL, Finnerty CC. Signaling from the membrane via membrane estrogen receptor-alpha: Estrogens, xenoestrogens, and phytoestrogens. Steroids. 2005;**70**(5-7 SPEC. ISS.):364-371

[9] Rodríguez EB, Flavier ME, Rodríguez-Amaya DB, Amaya-Farfán J. Phytochemicals and funcrional foods. Currem Situation and prospect for developing countries. Seguridad

[10] Crozier AM, Clifford N, Ashihara H. Plant Secundary Metabolites. Occurrence, Structure

[11] Tsao R. Chemistry and biochemistry of dietary polyphenols. Nutrients. 2010;**2**:1231-1246

[12] Duda-Chodak A, Tarko T, Satora, P, Sroka P. Interaction of dietary compounds, especially polyphenols, with the intestinal microbiota: A review. European Journal of Nutri-

[13] Philp HA. Hot flashes—a review of the literature on alternative and complementary

[14] Gaya P, Medina M, Sánchez-Jiménez A, Landete JM. Phytoestrogen metabolism by adult

[15] Landete JM, Arqués J, Medina M, Gaya P, de Las Rivas B, Muñoz R. Bioactivation of phytoestrogens: Intestinal bacteria and health. Critical Review in Food Science and Nutri-

[16] Landete JM. Ellagitannins, ellagic acid and their derived metabolites: A review about source, metabolism, functions and health. Food Research International. 2011;**44**(5):

[17] Cederroth CR, Nef S. Soy, phytoestrogens and metabolism: A review. Molecular and

[18] Landete JM. Plant and mammalian lignans: A review of source, intake, metabolism,

[19] Setchell KDR, Brown NM, Desai PB, Zimmer-Nechimias L, Wolfe B, Jakate AS, Heubi JE. Bioavailability, disposition, and dose-response effects of soy isoflavones when consumed by healthy women at physiologically typical dietary intakes. The Journal of

[20] Seeram NP, Aronson WJ, Zhang Y, Henning SM, Moro A, Lee RP, Sartippour M, Harris DM, Rettig M, Suchard MA, Pantuck AJ, Belldegrun A, Heber D. Pomegranate ellagitannin-derived metabolites inhibit prostate cancer growth and localize to the mouse pros-

[21] Landete JM, Arqués J, Medina M, Gaya P, de Las Rivas B, Muñoz R. Bioactivation of phytoestrogens: Intestinal bacteria and health. Critical Reviewsin Food Scienceand

[22] Larrosa M, González-Sarrías A, García-Conesa MT, Tomás-Barberán F, Espín JC. Urolithins, ellagic acid-derived metabolites produced by human colonic microflora, exhibit

intestinal bacteria and health. Food Research International. 2012;**46**:410-424

tate gland. Journal Agricultural and Food Chemestry. 2007;**55**:7732-7737

treatment approaches. Alternative Medicine Review. 2003;**8**:284-302

human gut microbiota. Molecules. 2016;**21**:1034. DOI: 10.339.

Alimentaria en Nutrició, Campinas. 2006;**13**:1-22

tion. 2015;**54**:325-341

100 A Multidisciplinary Look at Menopause

tion. 2016;**56**:1826-1843

Cellular Endocrinology. 2009;**304**:30-42

Nutrition. 2003;**133**(4):1027-1035

Nutrition. 2015;**56**:1826-1843

1150-1160

and Role in the Human Diet. Oxford, RU: Blackwell; 2006

[48] Tanmahasamut P, Vichinsartvichai P, Rattanachaiyanont M, Techatraisak K, Dangrat C, Sardod P. *Cimicifuga racemosa* extract for relieving menopausal symptoms: A randomized controlled trial. Climacteric. 2015;**18**:79-85

[36] Saleh MC, Connell BJ, Saleh TM. Resveratrol induced neuroprotection is mediated via both estrogen receptor subtypes, ER(α) and ER(β). Neuroscience Letters. 2013;**548**:217-221

[37] Vargas KG, Milic J, Zaciragic A, Wen K, Jaspers L, Nano J, Franco OH. The functions of estrogen receptor beta in the female brain: A systematic review. Maturitas. 2016. DOI:

[38] Lin AHY, Leung GPH, Leung SWS, Vanhoutte PM, Man RYK. Genistein enhances relaxation of the spontaneously hypertensive rat aorta by transactivation of epidermal growth factor receptor following binding to membrane estrogen receptors-alpha and activation of a G protein-coupled, endothelial nitric oxide synthase-dependent pathway.

[39] Lindsey SH, Chappell MC. Evidence that the G protein-coupled membrane receptor GPR30 contributes to the cardiovascular actions of estrogen. Gender Medicine. 2011;

[40] Pinto Patricia I, Estevao S, Dulce M, Andrade A, Santos, Soraia P, Deborah M. Tissue responsiveness to estradiol and genistein in the sea bass liver and scale. Journal of

Steroid Biochemistry and Molecular Biology. 2016;**158**:127-137. ISSN: 1879-1220

[41] Thomas P, Dong J. Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: A potential novel mechanism of endocrine disruption. Journal of Steroid Biochemistry and Molecular Biology. 2006;**102**(1-5 SPEC.

[42] Watson CS, Alyea RA, Cunningham KA, Jeng YJ. Estrogens of multiple classes and their role in mental health disease mechanisms. International Journal Women's Health.

[43] Roberts H, Hickey M. Managing the menopause: An update. Maturitas. 2016;**86**:53-58

[44] Brando AR, Shivakumar G, Freeman M. Perimenopausal depression. Hormones, antidepressants, psychotherapy-what would you recommend? Current Psychiatry. 2008;

[45] Poluzzi E, Piccinni C, Raschi E, Rampa A, Recanatini M, De Ponti F. Phytoestrogens in postmenopause: The state of the art from a chemical, pharmacological and regulatory

[46] Taylor M. Alternative medicine and the perimenopause an evidence-based review.

[47] Schellenberg R, Saller R, Hess L, Melzer J, Zimmermann C, Drewe J, Zahner C. Dose-Dependent Effects of the *Cimicifuga racemosa* extract Ze 450 in the treatment of climacteric complaints: A randomized, Placebo-Controlled Study. Evidence-Based Complement

perspective. Current Medicinal Chemistry. 2014;**21**:417-436

Alternative Medicine. 2012;**2012**:260-301

Obstetrics & Gynecology Clinics of North America. 2002;**29**:555-573

10.1016/j.maturitas.2016.05.014

**8**(6):343-354

102 A Multidisciplinary Look at Menopause

ISS.):175-179

2010;**2**:153-166

**7**:39-50

Pharmacological Research. 2011;**63**(3):181-189

[71] Estrada-Camarena E, Lopez-Rubalcava C, Hernandez-Aragon A, Mejia-Mauries S, Picazo O. Long-term ovariectomy modulates the antidepressant-like action of estrogens, but not of antidepressants. Journal of Psychopharmacology. 2011;**25**:1365-1377

[59] Colli MC, Bracht A, Soares AA, de Oliveira AL, Bôer CG, de Souza CG, Peralta RM. Evaluation of the efficacy of flaxseed meal and flaxseed extract in reducing menopausal

[60] Dew TP, Williamson G. Controlled flax interventions for the improvement of menopausal symptoms and postmenopausal bone health: A systematic review. Menopause.

[61] Lee MS, Shin BC, Yang EJ, Lim HJ, Ernst E. Maca (Lepidium meyenii) for treatment of

[62] Davinelli S, Scapagnini G, Marzatico F, Nobile V, Ferrara N, Corbi G. Influence of equol and resveratrol supplementation on health-related quality of life in menopausal women:

[63] Walf AA, Rhodes ME, Frye CA. Antidepressant effects of ERbeta-selective estrogen receptor modulators in the forced swim test. Pharmacology Biochemistry and Behavior.

[64] Lund TD, Lephart ED. Dietary soy phytoestrogens produce anxiolytic effects in the ele-

[65] Blake C, Fabick KM, Setchell KD, Lund TD, Lephart ED. Neuromodulation by soy diets or equol: Anti-depressive & anti-obesity-like influences, age- & hormone-dependent

[66] Hartley DE, Edwards JE, Spiller CE, Alom N, Tucci S, Seth P, Forsling ML, File SE. The soy isoflavone content of rat diet can increase anxiety and stress hormone release in the

[67] Patisaul HB, Burke KT, Hinkle RE, Adewale HB, Shea D. Systemic administration of diarylpropionitrile (DPN) or phytoestrogens does not affect anxiety-related behaviors in

[68] Russell AL, Grimes JM, Larco DO, Cruthirds DF, Westerfield J, Wooten L, Keil M, Weiser MJ, Landauer MR, Handa RJ, Wu TJ. The interaction of dietary isoflavones and estradiol replacement on behavior and brain-derived neurotrophic factor in the ovariectomized

[69] Kuiper GG, Gustafsson JA. The novel estrogen receptor-beta subtype: Potential role in the cell- and promoter-specific actions of estrogens and anti-estrogens. FEBS Letters.

[70] Rodríguez-Landa JF, Hernández-Figueroa JD, Hernández-Calderón BC, Saavedra M. Anxiolytic-like effect of phytoestrogen genistein in rats with long-term absence of ovarian hormones in the black and white model. Progress in Neuropsychopharmacology &

gonadally intact male rats. Hormones and Behavior. 2009;**55**:319-328

menopausal symptoms: A systematic review. Maturitas. 2011;**70**:227-233

A randomized, placebo-controlled study. Maturitas. 2017;**96**:77-83

vated plus-maze. Behavioural Brain Research. 2001;**913**:180-184

effects. BMC Neuroscience. 2011;**16**:12-28

rat. Neuroscience Letters. 2017;**640**:53-59

Biological Psychiatry. 2009;**33**:367-372

male rat. Psychopharmacology (Berl). 2003;**167**:46-53

symptoms. Journal of Medicine Food. 2012;**15**:840-845

2013;**20**:1207-1215

104 A Multidisciplinary Look at Menopause

2004;**78**:523-529

1997;**410**:87-90

[83] Abdul RS, Abdul KB, Hidayat BMT, Mohd MMA. Antidepressant-like effect of methanolic extract of *Punica granatum* (pomegranate) in mice model of depression. Journal of

[84] Shastry R, Sharma A, Sayeli V, Sheetal D. Screening of antidepressant activity of *Punica*

[85] Díaz MAG. Calidad nutracéutica de extractos de granada dulce y ácida y bioaccesibilidad de sus compuestos fenólicos en un modelo in vivo. PhD Proposal. 2014;**1**

[86] Choi DW, Kim JY, Choi SH, Jung HS, Kim HJ, Cho SY, Chang SY. Identification of steroid hormones in pomegranate (*Punica granatum*) using HPLC and GC–mass spectrometry.

[87] Middha SK, Usha T, Pande V. HPLC evaluation of phenolic profile, nutritive content, and antioxidant capacity of extracts obtained from *Punica granatum* fruit peel. Advances

[88] Van Elswijk D, Schobel UP, Lansky EP, Irth H, Van der Greef J. Rapid dereplication of estrogenic compounds in pomegranate (*Punica granatum*) using on-line biochemical

[89] Espín JC. Biological significance of the gut microbial ellagic acid-derived metabolites

[90] Auerbach L, Rakus J, Bauer C, Gerner C, Ullmann, R, Wilmmer H, Huber J. Pomegranate seed oil in women with menopausal symptoms: A prospective randomized, placebo-

[91] Shuid AN, Mohamed IN. Pomegranate use to attenuate bone loss in major musculoskeletal diseases: An evidence-based review. Current Drug Targets. 2013;**14**:1565-1578 [92] Mori-Okamoto J, Otawara-Hamamoto Y, Yamato H, Yoshimura H. Pomegranate extract improves a depressive state and bone properties in menopausal syndrome model ovari-

[93] Rodríguez M. Respuestas fisológicas moleculares y fitoquímicas de variedades *de Brassica oleracea* (grupo itálica) sometidas a estrés abiótico [Tesis recepcional de Doc-

[94] Álvarez PE, de la Rosa LA, González-Aguilar GA, Ayala-Zavala JF. Antioxidantes en

[95] Klejin MJ, Van Der YT, Wilson PW, Adlerercreutz H, Mazur W, Grobbe DE, Jacques PF. Intake of dietary phytoestrogens is low postmenopausal women in the United States:

[96] Nardini MD' Aquino N, Tomassi G, Gentili V, Di Felice M, Scaccini C. Inhibition of human Low-Density lipoprotein oxidation by Caffeic acid and other hydroxycinnamic

acid derivatives. Journal Free Radical Biology & Medicine. 1995;**19**(5):541-552

detection coupled to mass spectrometry. Phytochemistry. 2004;**65**:233-241

controlled, double blinded trial. Menopause. 2012;**19**(4):426-432

ectomized mice. Journal of Ethnopharmacology. 2004;**92**:93-101

alimentos y salud. México: Clave Editorial; 2012. pp. 97-289

The Framingham Study (1-4). Journal of Nutrition. 2001;**131**:1826-1832

Natural Products and Biomedical Research. 2015;**1**:16-20

*granatum* in mice. Journal Pharmacognosy. 2017;**9**(1):27-29

Food Chemistry. 2006;**96**:562-571

106 A Multidisciplinary Look at Menopause

in Pharmacological Sciences. 2013;**2013**:296236

urolithins. JournalHindawi. 2013; **2013**: 1-16

torado]. España: Universidad de Murcia; 2013

[123] Ambrosone CB, McCann SE, Freudenheim JL, Marshall JR, Zhang Y, Shields PG. Breast cancer risk in premenopausal women is inversely associated with consumption of broccoli, a source of isothiocyanates, but is not modified by GST genotype. Journal of Nutrition. 2004;**134**:1134-1138

[111] Bhagwat S, Haytowitz DB, Holden JM. USDA Database for the Isoflavone content of Selected Foods. Vol. 15. Maryland: US Department of Agriculture; 2008. pp. 43-49

[112] Márques A. Mejora genética en glucosinolatos en semillas de mostaza etíope (*Brassica*

[113] Mataíx J. Rodríguez-Navarrete J. Tratado de Nutrición y Alimentación. Alimentos fun-

[114] Kim DH, Jung HA, Park SJ, kim JM, Lee S, Choi JS, Cheong JH, Ko KH, Ryu JH. The effects of Daidzin and its aglycon, Daidzein, on the Scopolamine induced Memory Impairment in Male Mice. Archives of Pharmacal Research. 2010;**33**(10):1685-1690

[115] Navarro-Cruz AR, Vera-López O, Muñoz-Bedolla M, Melgoza-Palma N, Lazcano-Hernández M, Gómez CrisostomoMR, Romero Vázquez M. Estudio de la concentración de quercetina en las variedades de manzana (*Malus domestica*) Fuji, red delicius y delicia. Red de Revistas Cientificas de América Latina, el Caribe, España y Portugal.

[116] Naso L, Lezama L, Rojo T, González Baró AC, Williams-Patricia AM, Ferrer EG. Efectos antioxidantes del ácido clorogénico y su complejo con el catión oxovanadio. Journal

[117] Aguilera-Ortíz M, Reza-Vargas MC, CHew-Madinaveitia RG, Meza-Velázquez JA. Propiedades funcionales de las antocianinas. Revista de Ciencias Biológicas y de la

[118] Zhang JC, Yao W, Dong C, Yang C, Ren Q1, Ma M, Han M, Wu J, Ushida Y, Suganuma H, Hashimoto K. Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation. The Journal of Nutritional Biochemistry.

[119] Yao W, Zhang JC, Ishima T, Dong C, Yang C, Ren Q, Ma M, Han M, Wu J, Suganuma H, Ushida Y, Yamamoto M, Hashimoto K. Role of Keap1-Nrf2 signaling in depression and dietary intake of glucoraphanin confers stress resilience in mice. Scientific Reports.

[120] Townsend BE, Johnson RW. Sulforaphane reduces lipopolysaccharide-induced proinflammatory markers in hippocampus and liver but does not improve sickness behav-

[121] Townsend BE, Chen YJ, Jeffery EH, Johnson RW. Dietary broccoli mildly improves neuroinflammation in aged mice but does not reduce lipopolysaccharide-induced sickness

[122] Fowke JH, Longcope C, Hebert JR. *Brassica* vegetable consumption shifts estrogen metabolism in healthy postmenopausal women. Cancer Epidemiology, Biomarkers &

*carinata A. Braun*). Doctorado. Universidad de Córdoba; 2008

2010;**25**:901-910

108 A Multidisciplinary Look at Menopause

Salud. 2011;**12**:16-22

2017;**39**:134-144

2016;**6**:306-359

Spectroscopy Letters. 2010;**64**:1-7

ior. Nutritional Neuroscience. 2017;**20**:195-202

behavior. Nutrition Research. 2014;**34**:990-999

Prevention. 2000;**9**:773-779

cionales. 4th ed. Barcelona: OCEANO/ ergon (ed); 2009. Chapter 20

**Chapter 7**

## **The Benefits of Physical Activity on Climacteric Women**

Simoni T. Bittar, José O.R. de Macêdo, Elisio A. Pereira Neto, Hidayane G. da Silva, Patrick A.S. Pfeiffer, Janine A. Padilha, Wagner V. dos Santos and Maria do S. Cirilo‐Sousa

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68829

### **Abstract**

As the population ages, there is a need of developing ways to prevent or revert the del‐ eterious effects of aging, especially in climacteric women who suffer with the problems caused by hormonal changes. Exercise is a nonmedicated intervention that can be applied on that population. The benefits of physical activity can positively change body composi‐ tion, increase levels of muscular strength, balance, and functional capacity. Strength train‐ ing, aerobic exercise, whole body vibration, and aquatic exercises are some of the modalities that health professionals can prescript to these individuals. Although there are many studies about these exercises, a technique called blood flow restriction is emerging as an alternative to high load exercises but with the same benefits.

**Keywords:** climacteric women, exercise, body composition, strength, blood flow restriction

### **1. Introduction**

The aging process, also called senescence, is characterized by gradual and irreversible changes in an organism's structure and operation as a result of the time passing. The World Health Organization (WHO), in the end of the 1990s, adopted the term "active aging" to describe the process of the health, participation, and security opportunities. The aim of the active aging is to increase the expectation and quality of life to all the people who are aging, including the fragile, physically impaired, and the ones that require special care [1]. Data from the WHO indicate that in 2025, the life expectation in the developed countries will be 81 years; and 78 years in the ones that are in the development process [2].

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The word "health," according to the WHO, refers to the physical, mental, and social well‐ being where the organism works optimally without any disease. Therefore, in an active aging project, the politics and programs that promote mental health and social living are just as important as the ones that improve the physical health conditions. Furthermore, the indi‐ vidual will be able to stay physically active and able to work [2].

During the adult life, the physiological functions of our organism decline, which is part of the senescence. The capacity of protein synthesis reduces significantly, there is a decrease of the immunological functions and changes in the body composition. Also, in elderly, the motor performance falls down expressively as a result of physiological degeneration and extrinsic factors such as environment conditions, task requirements, state of the disease, life style, or the combination of these elements. More than just biological and physiological changes, the aging process brings loss of psychological and social character, as well as elderly isolation, with the understanding that they are no longer active, or the fact that they think that are an obstacle to their families what causes sadness, low self‐steam, even causing emotional diseases like depression [3].

In the middle‐age, about 45 years old, the non‐transmissible diseases are responsible for most part of the health complications and deaths. The researches show the risk of chronic diseases as the age advances, such as diabetes, cardiopathy, osteoarthritis, osteoporosis, and sarcopenia. However, what raises the risk of development of chronic diseases at older ages is smoking, sedentarism, inadequate diet, and hormonal alterations [1]. On the other hand, the enrolment in adequate physical activities, healthy diet, nonsmoking, not drinking alco‐ hol, and the right use of the medicaments prescribed by the doctor may prevent diseases and the functional fall, increase the longevity and the individual's quality of life. Regarding specifically the indication of physical activity for the population over 65 years, the American College of Sports Medicine (ACSM) [4] recommends that along with aerobic exercises (mod‐ erate or intense), 8–10 strength exercises must be performed, with 8–12 repetitions for each exercise, two time a week.

The reduction of the lean mass close to 50 years is more expressive in women than men. The peak of this reduction happens on the postmenopause period, when occurs the loss of skeletal muscle, which is related to the fall on the production of ovarian hormones (espe‐ cially, estrogen). The sarcopenia is a syndrome characterized by progressive and generalized reduction of the skeletal muscle mass associated with the loss of muscular strength, having as a consequence the physical impairment (reduction of muscular function and speed), fall in the quality of life and greater mortality. The European Study Group in Sarcopenia on the Elderly recommends that for the sarcopenia diagnostic the individual must have, necessarily, low lean mass associated with one of these two factors: low muscular function or strength. The preservation of the skeletal muscle mass is connected to the well‐being and the disease prevention in the elderly [5].

Among the events that happen during the aging process, the reduction on the mineral bone density has a particular important role for the possible development of osteoporosis in both the genders but mostly in the female. After 40 years, the annual bone loss average is from 2 to 3% and elevates to more than 5% in the early years of climacteric [6]. The WHO defines osteoporosis as the reduction of bone mass associated with the disarrangement of the bone microarchitecture resulting in increased fragility of the bone and an elevated fracture risk [2].

Women in the postmenopause, when submitted to an exercise program based on stretching, balance, strength exercises, and impact exercises associated with hormone therapy (HT), show greater bone mineral density on the femoral neck when compared to the women that only do hormone therapy [7]. The muscle strength reduces fracture risks caused by osteoporosis because it increases the bone mineral content, the strength supported by the noncontractile tis‐ sues (tendons and ligaments), improvement in the postural function, and decrease in the risk of fall. Some studies suggest that the growth of muscle mass leads to a rise on the muscular strength, stimulating the bone remodeling through the piezoelectric effect, which is the capac‐ ity of the bone to transform mechanic signals into electrical signals [8].

### **2. Body composition**

### **2.1. Lean and fat mass**

The word "health," according to the WHO, refers to the physical, mental, and social well‐ being where the organism works optimally without any disease. Therefore, in an active aging project, the politics and programs that promote mental health and social living are just as important as the ones that improve the physical health conditions. Furthermore, the indi‐

During the adult life, the physiological functions of our organism decline, which is part of the senescence. The capacity of protein synthesis reduces significantly, there is a decrease of the immunological functions and changes in the body composition. Also, in elderly, the motor performance falls down expressively as a result of physiological degeneration and extrinsic factors such as environment conditions, task requirements, state of the disease, life style, or the combination of these elements. More than just biological and physiological changes, the aging process brings loss of psychological and social character, as well as elderly isolation, with the understanding that they are no longer active, or the fact that they think that are an obstacle to their families what causes sadness, low self‐steam, even causing emotional diseases like

In the middle‐age, about 45 years old, the non‐transmissible diseases are responsible for most part of the health complications and deaths. The researches show the risk of chronic diseases as the age advances, such as diabetes, cardiopathy, osteoarthritis, osteoporosis, and sarcopenia. However, what raises the risk of development of chronic diseases at older ages is smoking, sedentarism, inadequate diet, and hormonal alterations [1]. On the other hand, the enrolment in adequate physical activities, healthy diet, nonsmoking, not drinking alco‐ hol, and the right use of the medicaments prescribed by the doctor may prevent diseases and the functional fall, increase the longevity and the individual's quality of life. Regarding specifically the indication of physical activity for the population over 65 years, the American College of Sports Medicine (ACSM) [4] recommends that along with aerobic exercises (mod‐ erate or intense), 8–10 strength exercises must be performed, with 8–12 repetitions for each

The reduction of the lean mass close to 50 years is more expressive in women than men. The peak of this reduction happens on the postmenopause period, when occurs the loss of skeletal muscle, which is related to the fall on the production of ovarian hormones (espe‐ cially, estrogen). The sarcopenia is a syndrome characterized by progressive and generalized reduction of the skeletal muscle mass associated with the loss of muscular strength, having as a consequence the physical impairment (reduction of muscular function and speed), fall in the quality of life and greater mortality. The European Study Group in Sarcopenia on the Elderly recommends that for the sarcopenia diagnostic the individual must have, necessarily, low lean mass associated with one of these two factors: low muscular function or strength. The preservation of the skeletal muscle mass is connected to the well‐being and the disease

Among the events that happen during the aging process, the reduction on the mineral bone density has a particular important role for the possible development of osteoporosis in both the genders but mostly in the female. After 40 years, the annual bone loss average is from 2 to 3% and elevates to more than 5% in the early years of climacteric [6]. The WHO defines

vidual will be able to stay physically active and able to work [2].

depression [3].

112 A Multidisciplinary Look at Menopause

exercise, two time a week.

prevention in the elderly [5].

The role of physical activity on body and fat mass control is extremely important. Studies demonstrated that there is a negative correlation between regular physical activities and body mass index (BMI). Since the exercise enhances energy expenditure, it plays an important part on reaching the ideal weight and body composition related to the health of elderly people. Therefore, the morbi‐mortality, associated with non‐transmissible chronic diseases, could be reduced with prevention, including physical activity as a change on the lifestyle to improve the aspects of body composition. Also, a reduction on the muscle mass on climacteric women results in a decrease of the basal metabolic rate, strength, and level of physical activity. However, it is already established that the reduction of these energetic needs is not followed by a decrease on the caloric ingestion, which causes a rise in the body fat mass with aging [9].

The aerobic exercise is a modality that has the power of promoting positive changes in the body composition. However, there is a need of controlling the intensity of the exercise because litera‐ ture shows that when realized with a very small load, it will not modify the aspects of body com‐ position [10]. A group of postmenopause women performed a 1‐hour walking protocol three times a week for 6 months at 60% of the maximum oxygen volume (VO2max) intake, whereas the other group performed walking 5 days a week for the same period but without controlling the intensity. Despite both the groups had shown reduction in fat mass and percentage, only the controlled one had decrease in the body mass.

Still regarding the effects of exercise on body composition, eight postmenopause women and seven men, aged between 61 and 77 years, caucasian, healthy and sedentary, with body mass index (BMI) with normal levels (24.8 kg/m2 ) performed a 26‐week resistance training protocol to upper and lower limbs and lumbar extensors, three times a week, two series of 10 rep‐ etitions for each exercise at 65–80% of one maximum repetition (1RM), totaling 45 min [11].

Another aspect that can interfere on the results of exercise on the body composition is the presence or absence of a certified supervisor for the physical activity. Recently, the effects of an exercise program composed of stretching, weight bearing, resistance training for upper and lower limbs, and leisure activities in postmenopause women were evaluated where one group had the supervision of a physiotherapist and the other did not have; the exercises were performed at home. The upper and lower limbs and total body lean mass of the supervised group was increased. On the other hand, that did not happen on the other group, showing that supervision is important to obtain the desired results and also to prevent injuries [12].

The effects of a 16‐week variable load resistance exercise protocol on body composition, associated with diet or not, were evaluated in 15 postmenopause women (50–69 years) who performed strength training three times a week with a load of 90% of 1RM [13]. The sample was divided according to the BMI: G1 (*n* = 7; IMC > 27 kg/m2 ) and G2 (*n* = 8; IMC < 27 kg/m2 ). Group 1 was submitted to the exercise protocol plus diet, whereas the other group did not have the diet controlled. The exercise‐only group did not show significant changes on body composition.  In that perspective, although the exercise can promote a lot of benefits to climacteric women, if other aspects such as the diet are not well controlled, these benefits may not appear.

### **2.2. Bone mass**

Positive effects of the exercise on the increase or maintenance of bone mineral density (BMD) were already observed in post menopause women with osteopenia or osteoporosis. However, the benefits depend on the type of exercise, intensity, frequency, and duration of the session [14].

Strength training can increase the mechanical stress on bone throughout the tendon promot‐ ing an osteogenic response and the piezoelectric effect, justifying the maintenance or increase of BMD. Because of that mechanism, forces of compression, tension, or torsion can generate electric signals that stimulate bone activity and deposition of minerals in stress points caused by muscle contraction. The muscle contraction can increase the BMD and, possibly, block the bone reabsorption [8, 15].

A positive linear relation between BMD and the increase of load during 1 year of strength training in postmenopause women was observed [16]. Exercise programs from low to mod‐ erate impact (running, walking, steps up‐and‐down) are more effective for the preservation of BMD on the lumbar area and femoral neck when combined with strength training than high‐impact exercises such as jumping [17].

Many meta‐analyses point out that high‐intensity aerobic and resistance exercises tend to be more effective for the increase of lumbar spine BMD than low‐intensity walking. Nevertheless, when there is an association between low‐intensity walking and a high‐cal‐ cium diet is also effective on elevating BMD. Furthermore, these exercises can promote a 2% elevation on the BMD of postmenopause women, which is a very important improvement in their bone health [18, 19].

Moderate aerobic exercise (50% of the maximum VO2 ) seems to be safe and easy to execute in osteoporotic women and effectively increase BMD of the lumbar spine after 12 months of intervention [20]. A well‐regulated bone metabolism is extremely important for the prevention and maintenance of the bone system properties. Likewise, a training program can help on the reduction of reabsorption bone biomarkers, reducing the risk of vertebral fracture up to 25%, even if the BMD does not increase significantly [21].

Another aspect that can interfere on the results of exercise on the body composition is the presence or absence of a certified supervisor for the physical activity. Recently, the effects of an exercise program composed of stretching, weight bearing, resistance training for upper and lower limbs, and leisure activities in postmenopause women were evaluated where one group had the supervision of a physiotherapist and the other did not have; the exercises were performed at home. The upper and lower limbs and total body lean mass of the supervised group was increased. On the other hand, that did not happen on the other group, showing that supervision is important to obtain the desired results and also to prevent injuries [12].

The effects of a 16‐week variable load resistance exercise protocol on body composition, associated with diet or not, were evaluated in 15 postmenopause women (50–69 years) who performed strength training three times a week with a load of 90% of 1RM [13]. The sample

Group 1 was submitted to the exercise protocol plus diet, whereas the other group did not have the diet controlled. The exercise‐only group did not show significant changes on body composition.  In that perspective, although the exercise can promote a lot of benefits to climacteric women, if other aspects such as the diet are not well controlled, these

Positive effects of the exercise on the increase or maintenance of bone mineral density (BMD) were already observed in post menopause women with osteopenia or osteoporosis. However, the benefits depend on the type of exercise, intensity, frequency, and duration of

Strength training can increase the mechanical stress on bone throughout the tendon promot‐ ing an osteogenic response and the piezoelectric effect, justifying the maintenance or increase of BMD. Because of that mechanism, forces of compression, tension, or torsion can generate electric signals that stimulate bone activity and deposition of minerals in stress points caused by muscle contraction. The muscle contraction can increase the BMD and, possibly, block the

A positive linear relation between BMD and the increase of load during 1 year of strength training in postmenopause women was observed [16]. Exercise programs from low to mod‐ erate impact (running, walking, steps up‐and‐down) are more effective for the preservation of BMD on the lumbar area and femoral neck when combined with strength training than

Many meta‐analyses point out that high‐intensity aerobic and resistance exercises tend to be more effective for the increase of lumbar spine BMD than low‐intensity walking. Nevertheless, when there is an association between low‐intensity walking and a high‐cal‐ cium diet is also effective on elevating BMD. Furthermore, these exercises can promote a 2% elevation on the BMD of postmenopause women, which is a very important improvement in

) and G2 (*n* = 8; IMC < 27 kg/m2

).

was divided according to the BMI: G1 (*n* = 7; IMC > 27 kg/m2

benefits may not appear.

114 A Multidisciplinary Look at Menopause

bone reabsorption [8, 15].

their bone health [18, 19].

high‐impact exercises such as jumping [17].

**2.2. Bone mass**

the session [14].

Besides the discrete effect of walking on the lumbar vertebrae BMD, there are other benefits related to that exercise. A 4‐hour walking per week showed to be associated to a 41% less hip fracture risk compared to less than 1‐hour per week [22]. In the same perspective, 40‐ minute brisk walking, three times a week, promoted a clinical improvement on the femoral neck BMD and a 35% reduction on the risk of fall on the elderly after 2 years of exercise [23]. **Table 1** sums up a few studies that investigated the benefits of exercise on body composition of climacteric women.

**Table 1.** Studies related to exercise and body composition in climacteric women.

### **3. Neuromuscular variables**

As an important consequence caused by the many endocrine, neuroendocrine, behavioral, and metabolic changes that occur on the climacteric period, the decline of neuromuscular variables is one of the most frequent that brings important alterations to the life of this popu‐ lation [24]. During this chapter, the term "neuromuscular variables" will be used to make ref‐ erence to all capacities that are related to neural stimulus and muscle health such as strength, agility, speed, flexibility, balance, and others.

There is a direct relation between muscle mass loss and strength decrease in women with more than 40 years. It is estimated that the muscle strength has a 15% fall on the period between 60 and 79 years, and 30% from the eighth life decade, with the lower limbs being more affected than the upper limbs [25, 26].

The diminution of muscle strength as a result of changes in the composition of the subtypes of muscle fiber, oxidative stress, variations of the growing hormone (GH), IGF‐1, insulin, among others, also leads to a reduction in other important physical capacities that depends on the strength [27]. Body balance, walking speed, stepping up‐and‐down, recovery after a stabil‐ ity loss and standing up from the chair are some examples of variables that, with the fall in strength, end up being negatively affected.

The Brazilian Society of Sports Medicine [28] published an official statement regarding physi‐ cal activity and women's health pointing that there is an inverse relation between exercising regularly and the main causes of death in menopause women. Thus, performing physical exer‐ cises regularly is the most effective way of avoiding strength loss, or try to regain part of the strength that was lost, similarly all the other capacities that depends on strength [26].

There are many types of exercise that promote benefits for the neuromuscular variables of climacteric women. Strength training, in general, is the most well‐studied and used to achieve that goal. To prescribe correctly the most adequate training, few factors are to be taken into con‐ sideration such as the number of repetitions, load, series, resting interval, seminal frequency and others. The American College of Sports Medicine [4] states that to have effective results with the strength training, the load should be bigger than 65% of one maximum repetition (1RM), three series with 8–12 repetitions for the main muscle groups of the upper and lower limbs should be performed, at least three times a week. Nonetheless, those training variables can be manipulated in many ways, allowing the creation of a lot of training programs.

It is also well‐known that training with higher intensities promote bigger changes. When com‐ paring a training protocol that followed all the statements of the ACSM, which means exercises that involved the main muscle groups from upper and lower body where one group trained at 40% and the other at 80% of 1RM, it was observed that despite the fact that both showed increase of strength and transverse muscle section, the high intensity group had significantly more gains. In addition, it is important to highlight that in this specific study, emphasis was given to exer‐ cises that activated muscles that had origin or insertion on the spine and femur aiming to ally the strength gain with the piezoelectric effect and, consequently, improve the bone mass, which can be an interesting way to potentialize the benefit of the resistance exercise [29].

Although muscle strength happens to be a variable relatively easy to increase or, at least, maintain, it must be highlighted that if the individual stops practicing the physical activity, the detraining also happens fast. To illustrate that 15 postmenopause women practiced strength exercises for upper and lower limbs for 8 weeks with a load of 80% of 1RM and that was effective to increase strength of the trained muscle groups. To analyze the detraining process, those women stopped training and re‐evaluated after 8 weeks. The average of strength loss was 4.5% after detraining. Yet, it is important to say that there was no difference between the strength before the training and after detraining [30]. Hence, the strength training is effective to climacteric women, but its benefits are easily lost in cases of abandoning the exercise program, pointing out the importance of developing strategies that increase the adherence of these women to the training.

**3. Neuromuscular variables**

*n* **Age**

116 A Multidisciplinary Look at Menopause

**(years)**

2001 [14] 35 53–77 Osteoporotic

2003 [7] 140 X Osteoporotic

2004 [20] 50 X Osteoporotic

agility, speed, flexibility, balance, and others.

more affected than the upper limbs [25, 26].

strength, end up being negatively affected.

As an important consequence caused by the many endocrine, neuroendocrine, behavioral, and metabolic changes that occur on the climacteric period, the decline of neuromuscular variables is one of the most frequent that brings important alterations to the life of this popu‐ lation [24]. During this chapter, the term "neuromuscular variables" will be used to make ref‐ erence to all capacities that are related to neural stimulus and muscle health such as strength,

only

months G2: control group

**Year Sample Exercise protocol Main results**

postmenopause women

postmenopause women

postmenopause women

**Table 1.** Studies related to exercise and body composition in climacteric women.

G1: daily walking + 2 series of 15 repetitions per day of exercises for trunk and lower limb muscles and ingestion of calcium and D vitamin G2: detraining group G3: control group

G1: hormone therapy + strength training G2: hormone therapy

G1: outside walking (50% VO2max, 1 h per day, 4 days a week, for 12

No difference on the BMD of the lumbar vertebral in none

↑ Percentage average BMD of the G1 when comparing the baseline to the 1st and 2nd

of the groups;

year of training

therapy

groups

There was a positive association between the amount of weight lifted and the BMD of the femur independent from factors such as age, weight, and hormone

There was no significant difference on the BMD of both

The bone marker NTX showed a reduction on the G1

**Stage**

There is a direct relation between muscle mass loss and strength decrease in women with more than 40 years. It is estimated that the muscle strength has a 15% fall on the period between 60 and 79 years, and 30% from the eighth life decade, with the lower limbs being

The diminution of muscle strength as a result of changes in the composition of the subtypes of muscle fiber, oxidative stress, variations of the growing hormone (GH), IGF‐1, insulin, among others, also leads to a reduction in other important physical capacities that depends on the strength [27]. Body balance, walking speed, stepping up‐and‐down, recovery after a stabil‐ ity loss and standing up from the chair are some examples of variables that, with the fall in

The Brazilian Society of Sports Medicine [28] published an official statement regarding physi‐ cal activity and women's health pointing that there is an inverse relation between exercising A group of researchers from the Idaho State University, United States, developed a training program called POWIR (Prevent Osteoporosis with Impact + Resistance) with the initial goal of bone improvement but was modified to improve strength and function also. The basis of this program is composed of a progressive training that uses dumbbells, barbells, and weighted vests as ways of applying resistance focusing on exercises for the lower limbs, hips, chest, and back [31]. This protocol was initially created to healthy climacteric women; however, it was also applied in postmenopause women who had breast cancer.

In this specific population, 106 women who went through breast cancer treatment were sepa‐ rated in two groups where one performed the POWIR protocol and the other an exercise program consisted only of stretching and flexibility, called FLEX. The intervention lasted for 1 year and in addition to the exercises already pointed, both groups performed home exercises one time per week. The POWIR was able to improve aspects such as muscle strength, walking speed, stand up from the chair, among others, showing to be an efficient and safe option for climacteric women, including the ones who had diseases like cancer [31].

Water exercises are another type of physical activity that can improve neuromuscular vari‐ ables of climacteric women and the changes may be similar to other exercises that are com‐ monly used on the daily practice of physiotherapists and personal trainers, such as elastic bands. A water exercises protocol with the same number of repetitions, rest interval, series, week frequency, duration (35–60 min) and for the same muscle groups of an elastic band pro‐ tocol promote the similar benefits for climacteric women [32].

Nevertheless, even with the same exercises, some differences still appear when comparing water exercises and elastic bands. The water exercises were more efficient on improving the performance on the 60‐second squats (65%) and abdominal crunch (28%), whereas the elas‐ tic bands were better to increase flexibility (44.19%) and performance on the knee push‐up (29.13%). Still, it is important to highlight that both protocols promoted benefits in all neuro‐ muscular variables [32]. When the protocol is well designed with heating, stretching, strength exercises, and cool down, there is no doubt that the benefits will appear, and both water exer‐ cises and strength training with elastic bands are effective to climacteric women.

In fact, to promote a muscle strength gain, it is necessary that the muscle contracts and so acti‐ vate mechanisms that promote protein synthesis. In more intense exercises such as strength training or water exercises, it is very easy to observe how the contraction needed to win a load stimulates muscle hypertrophy and strength gains. On the other hand, lighter activities such as whole body vibration training (WBVT) sessions also stimulate muscle contraction [33]. The most important mechanism activated is that the vibration has the capacity of stimulating senso‐ rial receptors that lead to a reflect activation of the motor units, similar to what happens on the tonic reflex [34].

Hormone therapy (HT) on climacteric women is an important treatment indicated to reduce the symptoms (such as, heat waves, night sweats, vaginal dryness, changes in sleep, among others) caused by decrease of hormones, mainly estrogen [35, 36]. Studies confirmed the posi‐ tive effects of this therapy on the quality of life and strength in postmenopausal women [37, 38]. Associated with HT, physical exercise can bring benefits to women's health after menopause, reduce fat mass and the risk of coronary diseases; increase strength, resistance, and flexibility [39–41]. Besides that, weight‐bearing, strength, and balance exercises associated with HT are able to help in osteoporosis prevention and treatment in a 1‐year period, aiming to increase BMD and, consequently, reducing the number of lumbar and femur neck fractures [16].

It is undeniable that the strength training is the type of exercise mostly used to promote strength gains. In this perspective, to see if the WBVT is also capable of promoting those gains, the results of both types of exercise must be compared. Three times a week WBVT and strength training, for 6 months, were able to increase significantly the isometric (15.10% and 16.49%, respectively) and isotonic (16.47% and 10.59%) strength, those differences being nonsignificant when comparing both types of training [34]. Thus, WBVT can promote a strength increase similar to the strength training. Some studies that analyzed the effects of many types of exer‐ cise on the neuromuscular variables are listed on **Table 2**.

**Table 2.** Studies related to exercise and neuromuscular variables in climacteric women.

one time per week. The POWIR was able to improve aspects such as muscle strength, walking speed, stand up from the chair, among others, showing to be an efficient and safe option for

Water exercises are another type of physical activity that can improve neuromuscular vari‐ ables of climacteric women and the changes may be similar to other exercises that are com‐ monly used on the daily practice of physiotherapists and personal trainers, such as elastic bands. A water exercises protocol with the same number of repetitions, rest interval, series, week frequency, duration (35–60 min) and for the same muscle groups of an elastic band pro‐

Nevertheless, even with the same exercises, some differences still appear when comparing water exercises and elastic bands. The water exercises were more efficient on improving the performance on the 60‐second squats (65%) and abdominal crunch (28%), whereas the elas‐ tic bands were better to increase flexibility (44.19%) and performance on the knee push‐up (29.13%). Still, it is important to highlight that both protocols promoted benefits in all neuro‐ muscular variables [32]. When the protocol is well designed with heating, stretching, strength exercises, and cool down, there is no doubt that the benefits will appear, and both water exer‐

In fact, to promote a muscle strength gain, it is necessary that the muscle contracts and so acti‐ vate mechanisms that promote protein synthesis. In more intense exercises such as strength training or water exercises, it is very easy to observe how the contraction needed to win a load stimulates muscle hypertrophy and strength gains. On the other hand, lighter activities such as whole body vibration training (WBVT) sessions also stimulate muscle contraction [33]. The most important mechanism activated is that the vibration has the capacity of stimulating senso‐ rial receptors that lead to a reflect activation of the motor units, similar to what happens on the

Hormone therapy (HT) on climacteric women is an important treatment indicated to reduce the symptoms (such as, heat waves, night sweats, vaginal dryness, changes in sleep, among others) caused by decrease of hormones, mainly estrogen [35, 36]. Studies confirmed the posi‐ tive effects of this therapy on the quality of life and strength in postmenopausal women [37, 38]. Associated with HT, physical exercise can bring benefits to women's health after menopause, reduce fat mass and the risk of coronary diseases; increase strength, resistance, and flexibility [39–41]. Besides that, weight‐bearing, strength, and balance exercises associated with HT are able to help in osteoporosis prevention and treatment in a 1‐year period, aiming to increase BMD and, consequently, reducing the number of lumbar and femur neck fractures [16].

It is undeniable that the strength training is the type of exercise mostly used to promote strength gains. In this perspective, to see if the WBVT is also capable of promoting those gains, the results of both types of exercise must be compared. Three times a week WBVT and strength training, for 6 months, were able to increase significantly the isometric (15.10% and 16.49%, respectively) and isotonic (16.47% and 10.59%) strength, those differences being nonsignificant when comparing both types of training [34]. Thus, WBVT can promote a strength increase similar to the strength training. Some studies that analyzed the effects of many types of exer‐

cise on the neuromuscular variables are listed on **Table 2**.

cises and strength training with elastic bands are effective to climacteric women.

climacteric women, including the ones who had diseases like cancer [31].

tocol promote the similar benefits for climacteric women [32].

tonic reflex [34].