medicina

Review
A Nutraceutical Approach to Menopausal Complaints
Pasquale De Franciscis 1 , Nicola Colacurci 1 , Gaetano Riemma 1 , Anna Conte 1 , Erika Pittana 1 ,
Maurizio Guida 2 and Antonio Schiattarella 1, *
1 Department of Women, Child and General and Specialized Surgery, University of Campania “Luigi
Vanvitelli”, 80138 Naples, Italy
2 Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples
“Federico II”, 80138 Naples, Italy
* Correspondence: [email protected]; Tel.: +39-392-165-3275




Received: 27 June 2019; Accepted: 24 August 2019; Published: 28 August 2019


Abstract: The menopausal transition, or perimenopause, is characterized by menstrual irregularities,

vasomotor symptoms, sleep disturbances, mood symptoms, and urogenital tract atrophy. These
changes can also affect the quality of life and one’s self-esteem. Hormone replacement therapy
(HRT) is considered the best option to achieve therapeutic relief of different menopausal symptoms
but is usually restricted to moderate or severe symptoms. Moreover, many women refuse HRT for
a variety of reasons concerning the fear of cancer and other adverse effects. According to these
considerations, new topics are emerging: Dissatisfaction with drug costs and conventional healthcare,
desire for personalized medicines, and the public perception that “natural is good”. In this context,
nonhormonal therapies are mostly evolving, and it is not unusual that women often request a “natural”
approach for their symptoms. The aim of this study is to investigate nonhormonal therapies that
have been identified to reduce the menopausal symptoms.

Keywords: nutraceuticals; menopausal symptoms; natural approach; supplementation; menopause;

isoflavones; Agnus castus; vasomotor symptoms; sleep disturbances

1. Introduction
The onset of menopause is one of the most critical phases in a woman’s life span and
is defined retrospectively as the time of the final menstrual period, followed by 12 months of
amenorrhea [1,2]. The age at menopause appears to be genetically determined and is unaffected
by race, socioeconomic status, age at menarche, or the number of prior ovulations [3]. Menopausal
transition, or ‘perimenopause’, is a defined period that begins with the onset of irregular menstrual
cycles until the last menstrual period and is followed by fluctuations in reproductive hormones [4,5].
This period is characterized by menstrual irregularities, and prolonged and heavy menstruation
intermixed with episodes of amenorrhea, vasomotor symptoms, insomnia, mood issues, and vaginal
dryness [6,7]. Hormone replacement therapy (HRT) represents the first choice in the treatment
of menopausal symptoms [8–11]. Moreover, perimenopause can be characterized by unknown
fears and ailments: Women can lose their confidence and self-esteem can get shattered with the
fast-establishing menopause [7,12]. More than 70 million women in the USA are affected by menopausal
symptoms [1,2,13]. Osteoporosis and cardiovascular disease represent the most important long-term
effects and seriously impact the quality of life of menopausal women [14,15]. However, nonhormonal
therapies are mostly developing and it is not unusual that women often request a “natural” approach for
their menopausal symptoms. Nutraceuticals, a pharmaceutical alternative with medicinal properties,
extracted from food or plants, belong to this approach [2,16–18].

Medicina 2019, 55, 544; doi:10.3390/medicina55090544 www.mdpi.com/journal/medicina

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2. Treatment Approaches
Hormone replacement therapy (HRT) is considered the best option to achieve therapeutic relief
of different menopausal symptoms [10,19]. U.S. Food and Drug Administration (FDA) indications
include HRT for vasomotor symptoms, for prevention of bone loss, for the genitourinary syndrome
of menopause, and for premature hypoestrogenism [10,20–23]. Appropriate treatment includes an
early administration of HRT before the age of 60 and up to ten years of amenorrhea [10,11,13,24].
Customization of the dose, routes of administration, types of combination, annual controls, and a
treatment duration less than five years are guarantees of a good risk/benefit ratio [10]. The estrogens
prescribed are mainly ethinyl estradiol, conjugated equine estrogens (CEE), synthetic conjugated
estrogens, and micronized 17b-estradiol [10,13]. Progestogen is used to prevent endometrial
thickening and the increase of risk of endometrial cancer during estrogen therapy [10,25]. Progestins
more often prescribed are medroxyprogesterone acetate (MPA), norethindrone acetate, and native
progesterone [10,26]. Bazedoxifene is a new compound that belongs to the selective estrogen receptor
modulators (SERM) and is used with CEE to improve the tissue selectivity [27,28]. However,
the appropriate dose of HRT should be determined individually in order to reduce adverse effects,
such as fluid retention, nausea, headaches, breast tenderness, bloating, leg cramps, and vaginal
bleeding [10,11,14,15,29,30]. Nevertheless, HRT use is usually restricted to moderate or severe
symptoms [10,19,31]. Absolute contraindications are represented by undiagnosed abnormal vaginal
bleeding, active thromboembolic disorder or acute-phase myocardial infarction, suspected or active
breast or endometrial cancer, and active liver disease with abnormal liver function tests [19,32].
Endometriosis is considered as a relative contraindication; in fact, the absolute risk of disease
recurrence and malignant transformation is unknown, and the impact of HRT use on these outcomes
is difficult to quantify [33–35]. Even if it is well-known that HRT is the gold standard treatment for
symptomatic menopausal women, it has been reported that less than 30% of menopausal women
take HRT and only 15% continue the therapy for a prolonged period [36–38]. Twenty-five percent
of women remain symptomatic for more than five years, and almost 15% of the 60s and 9% of the
70s have significant vasomotor symptoms; in these kinds of patients, there is no agreement to use
HRT [39]. Moreover, many women refuse HRT for a variety of reasons concerning the fear of cancer and
adverse effects such as weight gain [40]. Alongside these considerations, new concepts are emerging:
Consumers’ dissatisfaction with drug costs and conventional healthcare, desire for personalized
medicines, the turn to natural products for treatment and prevention, a new focus on preventive
medicine, and the public perception that “natural is good” [2,16,37,41–43], as reported in Figure 1.
In such a scenario, nonhormonal therapies are mostly developing, and it is not unusual that
women often request a “natural” approach for their symptoms. Apart from much personal skepticism,
the ability to listen and to grasp the needs of patients is particularly relevant in menopausal women who
are going through this critical phase of life [3,44]. This aspect, which has so far been underestimated,
has recently been investigated, highlighting the needs of women about the topic: Women want
their healthcare providers to start listening to what they report, want to discuss and seek help for
nonvasomotor menopause-related symptoms, and want clear evidence-based information about the
various hormonal and nonhormonal treatment options [40,44]. In the last years, nutraceuticals have
gained immense popularity when compared with HRT due to their claimed ability to relieve menopausal
symptoms [45,46]. Nutraceuticals are foods, parts of foods, and botanicals that provide medical or health
benefits, including the prevention and treatment of disease [47,48]. The term “nutraceutical” comes
from two words: “nutrient” (food component) and “pharmaceutical” (medical drug) and the name was
coined in the last century by Stephen De Felice, founder and chairman of the Foundation for Innovation
in Medicine, an American nonprofit organization [49]. The philosophy behind nutraceuticals was
probably introduced in Asia throughout ancient China and then improved and defined by physicians
of Kampo medicine, the study of traditional Chinese medicine in Japan, especially since the seventh
century [50]. Kampo has a holistic therapeutic approach, as it considers the mind and body like
one entity: The therapeutic aim is to alleviate symptoms and to bring back harmony in bodily
Medicina 2019, 55, 544 3 of 17

functions [51–53]. However, the traditional Chinese medicine (TCM) includes several therapeutic
approaches, such as acupuncture and moxibustion, for menopausal complaints [54–56]. Moreover, in
TCM, menopause is considered as a kidney dysfunction [55,56]. This organ is firstly conceptualized as
responsible for fluid balance, temperature, and fertility; and secondly, impacts the function of the heart,
spleen, and liver, the latter being considered as the center of emotions [55,56]. For the determination of
the appropriate herbal prescription, the physician investigates the complaints and symptoms of the
patient, including taking their temperature, examining sensation, weakness, or sweating, symptoms
which are not often primarily taken into account in conventional medicine [50,57]. To date nutraceuticals
include: Dietary supplements (substances which have established nutritional functions able to affect
structure and function of body such as vitamins, minerals, amino acids, fatty acids, probiotics, prebiotics,
antioxidants, enzymes, coenzyme Q, carnitine, etc.), herbal medicines (isoflavones, pollen extracts,
cimicifuga, red clover, etc.), functional foods—any modified food or ingredient that may provide a
benefit (prebiotics-oligofructose, omega-3, canola oil, stanols), and medicinal foods (transgenic cows
and lactoferrin for immune enhancement, transgenic plants for oral vaccination against infectious
diseases, health bars with added medications). Among these, herbal medicines including isoflavones,
black cohosh, red clover, pollen extracts, and others may be used in symptomatic menopausal women.
In the US and Britain, surveys show that 80% of peri- and postmenopausal women are current or
former users of dietary supplements [58]. However, the benefits of these compound have yet to be
demonstrated with certainty, and these regimens are not completely free from side effects [8,37,59–61].
Nutraceuticals are considered differently depending on a country’s legislation. In the European
community, they are placed in the middle ground between drugs and food: They are extracted from
food or plants with medicinal properties [18,47]. In this scenario, nutraceuticals have a role in the
management of symptomatic menopausal women.

Figure 1. Nutraceutical and the choice of menopausal therapy. Nonhormonal therapies represent
a developing option that is characterized by medical information and discussion with the patient.
The customization of the therapy is a fundamental point and depends on many factors, clinical and
not, such as previous therapies, risk factors, and type of symptoms. Points of strength in nutraceutical
choice are: They are user-friendly, are useful as a first approach to menopausal complaints, can be used
together with drugs, and are useful if HRT is refused or contraindicated.
Medicina 2019, 55, 544 4 of 17

3. Phytoestrogens
Phytoestrogens are presently the most popular form of alternative therapy for support of
menopausal symptoms, besides HRT [62,63]. They are plant-based compounds in about 300 plants [35].
Its name comes from the Greek word phyto (“plant”) and estrogen. The main classes are isoflavones
(active in humans), lignans (active in humans), cumestan, and lactones [64]. Food sources are various:
soy flour, legumes, fruits and vegetables, cereals, olive oil, wheat, etc. Their chemical structure and
efficacy are almost similar to oestradiol [63].

Isoflavones
Isoflavones are the most important compound of phytoestrogens and are produced almost
exclusively by the members of the Fabaceae like bean. It includes daidzein, genistein, biochanin A,
formononetin, and glycitein [63]. They showed agonist–antagonist estrogen action and exerted elective
stimulation of β-estrogen receptors (βERs) with less affinity and lower potency than estrogens [64].
Moreover, they stimulate the synthesis of sex hormone binding globulin (SHBG); therefore, safety in
long-term use could be expected [63]. The examination of meta-analyses of randomized controlled
trials to evaluate the effectiveness of phytoestrogens in vasomotor symptoms and their side effects in
postmenopausal women revealed considerable divergence among authors [63]. Nevertheless, most
reported mitigation of the symptoms, as well as improvement in the quality of life; none reported
any side effects. Another recent review argued that no conclusive evidence showed a benefit of
phytoestrogen-enriched or -derived products for menopausal vasomotor symptoms, except for
products containing a minimum of 30 mg per day of genistein [64]. It is well known that the absorption
of the soy isoflavones depends on the presence of the intestinal flora that are capable of producing
glycosidases and therefore to hydrolyze genistein and daidzin to the active aglycons [65,66]. Taking
this into consideration, it has been suggested to combine soy isoflavones with lactic acid bacteria in
the form of spores, resistant to the gastric and biliary secretion, to assure the bioavailability of soy
isoflavones [67,68]. The association with probiotic was also studied for symptoms of genitourinary
syndrome of menopause, but results were not satisfactory [69]. Isoflavones exert a limited beneficial
effect on cognition, as increased choline acetyltransferase and brain-derived neurotrophic factor in the
hippocampus and frontal cortex [70]. However, this effect may be modified by age, gender, ethnicity,
menopausal status, and length of treatment [70]. The effects on bone metabolism are interesting due to
a significant decrease in bone resorption process, especially if associated with HRT [26]. Moreover, the
topical application showed a good effect on vaginal health and dyspareunia. Finally, several studies
showed a significant effect on the lipid profile and inflammatory marker associated, with a lower risk
of cardiovascular disease [71,72].

4. Herbal Derivatives
Herbal remedies are frequently used to alleviate menopause symptoms and are effective in the
treatment of acute menopausal syndrome with different mechanisms [73]. One of the major problems
is that people usually take herbal therapies in the form of supplement pills and not as a preparation
made directly from the herb by a trained herbalist [74]. Moreover, herbal supplements are not as
strictly regulated as prescription drugs and quality, safety, and purity may vary between brands or
even between bundles of the same brand [75]. These compounds may also interact with prescription
drugs, resulting in dangerous changes in the effect of the drug [74,75]. Here below a list of the herbs
most frequently used in the treatment of menopausal symptoms, also reported in Table 1.

4.1. Actaea racemosa

This herb, also called Cimicifuga racemosa or black cohosh or fairy candle, has a long history of use:
Native Americans used it to treat many diseases like musculoskeletal pain, fever, cough, pneumonia,
sluggish labor, and menstrual irregularities [76]. It’s among the most studied herbal derivatives with
Medicina 2019, 55, 544 5 of 17

observational studies during the 50s and 70s, and controlled studies since the 80s for a total of 11,073
patients. Black cohosh showed a positive effect in treating hot flashes and other menopausal symptoms
like sleep quality. According to a recent study, the herb can also inhibit the growth of the myomas,
in contrast to tibolone in patients with uterine myomas [77]. However, evidence on the safety of black
cohosh was inconclusive, owing to poor reporting. A review argued that there is insufficient evidence
to support the use of black cohosh for menopausal symptoms, particularly concerning allocation
concealment and the handling of incomplete data from studies [78]. When looking at recent data,
evidence of effectiveness for black cohosh has improved, with good evidence existing for standardized
isopropanolic extract preparations of this herb, such as those approved for use in treatment in many
European countries [76]. Terpene glycosides are the active compounds and bind to the estrogen
receptor and selectively suppress the secretion of LH without any effect on FSH. Gastrointestinal side
effects are the most common and there has been some concern about hepatotoxicity with long-term use
of black cohosh [76,77].

4.2. Evening Primrose Oil

Also called Oenothera biennis oil, it contains omega-6 fatty acids, which increase prostaglandin
E2 that has anti-inflammatory effects [79]. The main application is for systemic diseases marked by
chronic inflammation, such as atopic dermatitis and rheumatoid arthritis [80]. It is often used for
several complaints such as menopausal and premenstrual symptoms [79]. However, several studies
showed that the compound has no benefit in treating menopausal flushing compared with placebo [80].
Oenothera biennis oil may cause mild gastrointestinal side effects or lower seizure threshold in patients
taking antiepileptic drugs [79,80].

4.3. Foeniculum vulgare

The common name of this herb is Fennel. It is characterized by the presence of palmitic acid and
beta-sitosterol and shows antiandrogenic and anti-inflammatory effects [81,82]. Its main application
is on hot flashes in postmenopausal women but it can also help anxiety in those patients with
depression [81]. Vaginal fennel ethanol extract cream showed an improvement of vaginal atrophy and
sexual functions in menopause women due to its estrogenic effects [83]. No critical side effects have
been reported [81,83].

4.4. Ginkgo biloba

The herb was used in the treatment of attention disorders in postmenopausal women, but several
studies reduced its positive action [84]. However, a recent study showed a positive effect on the sexual
desire of menopausal women [85]. The side effects include mild gastrointestinal disorders, allergic
reactions, headache, and lowering of seizure threshold [84,85].

4.5. Glycyrrhiza glabra

It is more famously called licorice and contains terpenes, saponins, flavonoids, isoflavonoids,
and steroids [86]. It has various levels of estrogenic activities, and one clinical trial study showed
that it is more effective than HRT in improving hot flash duration [86]. However, HRT can reduce
the duration and severity of hot flashes more than licorice [86]. Prolonged use of this herb can cause
cardiovascular disease, hypercortisolism, hypokalemia, and hypernatremia and safety studies are
necessary [87].

4.6. Hypericum perforatum

The herb, also called St. John’s Wort, showed a positive effect on the treatment for the vasomotor
symptoms of postmenopausal women [88]. A study found a chemopreventive effect in human breast
cancer cells through AMPK/mTOR signaling [89]. A systematic review showed that the combination
Medicina 2019, 55, 544 6 of 17

of this compound with C. racemosa demonstrated a positive effect on climacteric complaints [90].
The side effects are fewer and include gastrointestinal discomfort, sensitivity to light, restlessness,
and fatigue [91].

4.7. Medicago sativa

Also called Alfalfa, this herb contains noncellulosic polysaccharides that exert various effects:
Immunomodulatory, anti-inflammatory, antioxidant/anticancer, and growth-promoting bioactivities
and, in addition, it seems to reduce the incidence of chronic disease [92]. It also shows a slight effect
on neurovegetative menopausal symptoms [93]. Some critical side effect besides the infection were
salmonella, escherichia coli, and listeria, which reduced its use [94,95].

4.8. Melissa officinalis

This herb, also known as lemon balm, bee balm, or honey balm, has long been used as a
medicinal plant but also as a vegetable and to add flavor to dishes [96]. It contains volatile compounds,
triterpenoids, phenolic acids, and flavonoids [97]. It has been used for the treatment of a wide range of
diseases, especially anxiety and some other mental disorders [98]. It shows many pharmacological
effects, such as anxiolytic, antiviral, antioxidant, and antispasmodic activities but also exerts action
on the central nervous system, mainly on cognition and memory [99,100]. One of its derivatives is
caffeic acid, and no dangerous side effects are reported in the literature; however, confirmatory trials
are warranted to substantiate these effects in the clinical setting [101].

4.9. Panax ginseng

Anti-inflammatory properties characterize this plant, and a recent review of randomized clinical
trials showed promising results for improving glucose metabolism and moderating the immune
response [102]. Possible mechanisms of action of ginseng include hormonal effects related to those of
estrogen with a slight effect on depression, mood disorders, and sexual function [103]. The principal
active compounds are ginsenosides, which have been shown to exert estrogen-like actions [104,105].
However, side effects are not clear at all, and more studies are requested to assess the effects on hot
flash frequency and endometrial thickness [106].

4.10. Passiflora incarnata

Also called passion fruit, it has long been used in traditional herbal medicine for the treatment
of insomnia and anxiety, but also a sedative tea in North America [107]. This plant showed
analgesic, anti-spasmodic, anti-asthmatic, wormicidal, and sedative actions, but it is also used
for dysmenorrhea [107]. It has been proposed to treat early menopausal symptoms such as insomnia,
vasomotor symptoms, depression, anger, or headaches [108]. The plant has a good safety profile,
and no particular side effects have been reported in the literature, although more studies are needed to
widely assess this aspect [109].

4.11. Pimpinella anisum

Pimpinella anisum, also known as anise, contains an active compound with both estrogenic and
analgesic, antioxidant, antimicrobial, anticonvulsant, and antispastic properties [110,111]. Moreover,
anise exerts activity on the gastrointestinal system with an antiulcer action while the aromatic
effects have been demonstrated in the palliation of nausea [110,112]. The primary therapeutic target
in menopause is against hot flashes [111]. No dangerous side effects have been reported in the
literature [113].
Medicina 2019, 55, 544 7 of 17

Table 1. Main characteristic of herbal derivatives used to alleviate menopause symptoms.

Herbal Derivatives
Scientific Name Common Name Effects Side Effects References
Treatment of menopause
symptoms such as hot flash,
Gastrointestinal
Actaea racemosa Black cohosh insomnia, irritability, but also [76,77]
discomfort.
musculoskeletal pain, fever,
cough.
Treatment for menopausal and Gastrointestinal
Evening Primrose Oenothera premenstrual symptoms, but also disorders and
[79,80]
Oil biennis oil for atopic dermatitis and interaction with
rheumatoid arthritis. antiepilectic drugs.
Treatment of hot flashes, anxiety, No side effects
Foeniculum vulgare Fennel [81–83]
and vaginal atrophy. reported.
Gastrointestinal
disorders, allergic
Treatment of attention disorders
Ginkgo biloba Ginkgo reactions, headache, [84,85]
in postmenopausal women.
and lowering of
seizure threshold.
Cardiovascular disease,
hypercortisolism,
Glycyrrhiza glabra Licorice Treatment of hot flash duration. [86,87]
hypokalemia, and
hypernatremia.
Treatment for the vasomotor Gastrointestinal
Hypericum
St. John’s Wort symptoms of postmenopausal disease, sensitivity to [88–91]
perforatum
women. light, fatigue.
Possible infection with
Effect on neurovegetative Salmonella,
Medicago sativa Alfalfa [92–95]
menopausal symptoms. Escherichia coli, and
Listeria.
Lemon balm, bee
Melissa officinalis balm or honey Effect on anxiety. No side effect reported. [96,98–101]
balm
Treatment of sleep disorders, Possible effect on
Panax ginseng Ginseng [102–106]
depression, and sexual function. endometrial thickness.
Treatment of vasomotor
Passiflora incarnata Passion fruit symptoms, insomnia, anxiety and No side effect reported. [107–109]
dysmenorrhea.
Treatment of hot flashes but it also No side effects
Pimpinella anisum Anise [110–113]
exerts an antiulcer action. reported.
Possible interaction
Treatment of hot flashes and
Salvia officinalis Sage herb with diabetes and [114–116]
sweats.
blood pressure.
Treatment of hot flashes and it No side effects
Trifolium pretense Red clover [117–120]
also exerts a bone preventing loss. reported.
Treatment for hot flashes and No particularly side
Trigonella foenum Fenugreek [121,122]
osteopenia. effects.
Useful for hot flashes, anxiety,
No side effects
Valerian officinalis Valerian sleep disorders and [123–125]
reported.
dysmenorrhea.
Chaste tree,
Treatment for vasomotor
Vitex agnus-castus chasteberry or Not reported. [126–128]
symptoms and sleep diseases.
monk’s pepper

4.12. Salvia officinalis

Also called sage herb, the mechanism of action is exerted through modulation of GABA receptors
and serotonin transporters, which impacts on hot flashes and sweats [114]. The active compound
inhibits choline esterase in vitro, explaining why excessive use may cause a feeling of warmth,
Medicina 2019, 55, 544 8 of 17

tachycardia dizziness, and epilepsy-like seizures [115]. However, the impact on diabetes and blood
pressure drugs are still not clear [116].

4.13. Trifolium pretense

Also known as red clover, the oral intake of supplements containing isoflavones of this plant has
been reported to be effective in reducing the frequency and severity of hot flashes [117]. Moreover,
it shows a chondroprotective effect on inflammation and may be used for preventing osteoporosis [118].
However, this herb is contraindicated with the concomitant use of hormonal drugs [119]. No apparent
evidence of adverse events has been shown during short-term use, but there are not enough data on
the safety of long-term administration [120].

4.14. Trigonella foenum

This herb, also called fenugreek, has been used to treat hot flashes, with some preliminary evidence
for prevention of menopausal induced osteopenia [121]. Moreover, some studies have focused on its
action for diabetes and dysthyroidism [122]. It contains compounds of mucilage, proteins, and steroidal
saponins [121]. No particular dangerous side effects have been reported [121,122].

4.15. Valerian officinalis

It is a traditional herb used for the treatment of anxiety and sleep disorders. It showed a sedative
effect, probably due to the increase of GABA in the synaptic cleft due to inhibition of its reuptake [123].
It has direct inhibitory effects on the contractility of the human uterus, justifying the traditional use in
the treatment of uterine contractions associated with dysmenorrhea [124]. Moreover, this herb is used
in the treatment of hot flashes in menopause [125]. No critical side effects have been reported [124,125].

4.16. Vitex agnus-castus

Vitex agnus-castus (also called chaste tree, chasteberry, or monk’s pepper) increases melatonin
release, interacts with opioid receptors, and can play a role in vasomotor symptoms and sleep
diseases [126]. It has been used for dysmenorrhea, premenstrual dysphoric disorder, infertility, acne,
cyclic breast pain, and diarrhea and flatulence [127]. A recent study showed that V. agnus-castus and
magnolia, combined with Soy isoflavones + lactobacilli, improve quality of sleep in symptomatic
women [128].

5. Vitamins
The beneficial effect of vitamins for the treatment of perimenopausal symptoms is limited in the
literature [129,130]. Vitamin E could play a decisive role in the prevention of hot flushes if consumed
in the amount of 800 IU/day [130]. The protective effect of vitamins E on sleep quality has been recently
shown [131]. It could also be an alternative to vaginal estrogen in relieving the symptoms of vaginal
atrophy in postmenopausal women [132–134]. In postmenopausal women with vitamin D deficiency,
isolated supplementation of vitamin D3 were associated with a reduction in the metabolic syndrome
risk profile, but also with a lower risk of hypertriglyceridemia and hyperglycemia [135–137]. Recent
studies focused on other micronutrients such as essential fatty acid, B vitamins, vitamin C, magnesium,
and zinc to reducing stress and anxiety [138,139].

6. Other Compounds
Recent evidence suggested the role of other sources such as polyphenols extracted from hop
or grape seed or lipoproteins of marine origin [140–143]. These compounds showed a positive
role in the relief of menopausal symptoms, especially for vasomotor ones but also other positive
effects [140,142,144,145].
Medicina 2019, 55, 544 9 of 17

7. Discussion
HRT represents the first therapeutic option for menopausal symptoms, and its use is supported
by a large body of evidence and recommendations of scientific organizations [10,62]. On the contrary,
clinical trials about nutraceuticals suffers from some limitations: Uncommon and poorly comparable
results, a clear qualitative difference between the available products, a difficult definition of active
ingredients, a variable absorption, a different metabolization with the variable presence of active
principles, all leading to very variable clinical effects [17,37,146–149]. Moreover, it needs to be underlined
that placebo in all studies can reduce vasomotor symptomatology in between 20% and 50% of women
by reducing the intensity of symptoms by more than 30% [64,72]. To be considered effective against
vasomotor symptoms, therapies must overcome these “placebo-effects”. Otherwise, we can say
that they work as a costly placebo, for which harm cannot be guaranteed without proper studies.
Therefore, there is a need for further extensive studies on nutraceutical used for menopausal symptoms.
To date, it is a good practice to choose products from factories with good manufacturing practices as
for conventional drugs, guaranteeing a consistent, standardized composition and clinical studies to
support effectiveness and safety.

8. Conclusions
Health care providers should include in discussion with their patients all the available approaches
for relief of menopausal symptoms, giving all the information useful for a conscious and shared
choice, for real customization of the approach to the complaints in this critical phase of a woman’s
life. In this perspective, the nutraceuticals have their strengths because they are “simple to use and
user-friendly” with no need for specialist skills, and they represent a concrete choice for women who
cannot take HRT [36,38,40,150–153]. However, managing menopausal disturbances with nutraceutical
remedies requires an evidence-based approach. In particular and limited contexts, as indicated for
symptomatic women, nutraceuticals are useful as a tentative approach during diagnostic work-up
until the final prescription of HRT, for contraindications to or refusal of HRT, in combination with
pharmacological treatments.

Author Contributions: Conceptualization, P.D.F. and A.S.; investigation, A.C. and A.S.; resources, E.P.; data
curation, A.S.; writing—original draft preparation, A.S. and G.R.; writing—review and editing, M.G. and N.C.;
supervision, N.C.
Funding: This article received no external funding.
Conflicts of Interest: Authors declare no conflict of interests, commercial or financial in writing this article.

References
1. Soules, M.R.; Sherman, S.; Parrott, E.; Rebar, R.; Santoro, N.; Utian, W.; Woods, N. Executive summary:
Stages of reproductive aging workshop (STRAW). Fertil. Steril. 2001, 76, 874–878. [CrossRef]
2. Bajwa, S.; Singh, A.; Bajwa, S.J. Nutritional facts and menopausal symptomatology: The role of nutraceuticals.
J. Med. Nutr. Nutraceuticals 2012, 1, 42–49. [CrossRef]
3. Ainsworth, A.J.; Baumgarten, S.C.; Bakkum-Gamez, J.N.; Vachon, C.M.; Weaver, A.L.; Laughlin-Tommaso, S.K.
Tubal Ligation and Age at Natural Menopause. Obstet. Gynecol. 2019, 133, 1247–1254. [CrossRef] [PubMed]
4. Li, R.-L.; Shen, X.-L.; Xu, F.; Shui, X.-J.; Chen, Y.-M.; Wang, W.-H.; Zheng, J.-Y. Evaluation of ovarian function
using three dimensional ultrasound in perimenopausal women. Gynecol. Endocrinol. 2019. [CrossRef]
[PubMed]
5. De Franciscis, P.; Cobellis, L.; Fornaro, F.; Sepe, E.; Torella, M.; Colacurci, N. Low-dose hormone therapy in
the perimenopause. Int. J. Gynecol. Obstet. 2007, 98, 138–142. [CrossRef] [PubMed]
6. Jutras, M.L.; Cowan, B.D. Abnormal bleeding in the climacteric. Obstet. Gynecol. Clin. N. Am. 1990, 17,
409–425.
Medicina 2019, 55, 544 10 of 17

7. Gregersen, N.; Jensen, P.T.; Giraldi, A.E. Sexual dysfunction in the peri- and postmenopause. Status of
incidence, pharmacological treatment and possible risks. A secondary publication. Dan. Med. Bull. 2006, 53,
349–353. [PubMed]
8. Hill, D.A.; Crider, M.; Hill, S.R. Hormone Therapy and Other Treatments for Symptoms of Menopause.
Am. Fam. Physician. 2016, 94, 884–889.
9. Santoro, N. Perimenopause: From Research to Practice. J. Women Health 2016, 25, 332–339. [CrossRef]
10. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position
statement of The North American Menopause Society. Menopause 2017, 24, 728–753. [CrossRef]
11. Manson, J.E.; Chlebowski, R.T.; Stefanick, M.L.; Aragaki, A.K.; Rossouw, J.E.; Prentice, R.L.; Anderson, G.;
Howard, B.V.; Thomson, C.A.; LaCroix, A.Z.; et al. Menopausal hormone therapy and health outcomes
during the intervention and extended poststopping phases of the Women’s Health Initiative randomized
trials. JAMA 2013, 310, 1353–1368. [CrossRef] [PubMed]
12. Liu, Z.; Ho, S.C.; Xie, Y.J.; Chen, Y.; Chen, Y.; Chen, B.; Wong, S.Y.; Chan, D.; Wong, C.K.; He, Q.; et al.
Associations between dietary patterns and psychological factors: A cross-sectional study among Chinese
postmenopausal women. Menopause 2016, 23, 1294–1302. [CrossRef] [PubMed]
13. Marsden, J. British Menopause Society consensus statement: The risks and benefits of HRT before and after a
breast cancer diagnosis. Post Reprod. Health 2019, 25, 33–37. [CrossRef] [PubMed]
14. Marjoribanks, J.; Farquhar, C.; Roberts, H.; Lethaby, A.; Lee, J. Long-term hormone therapy for perimenopausal
and postmenopausal women. Cochrane Database Syst. Rev. 2017, 1, CD004143. [CrossRef] [PubMed]
15. Gurney, E.P.; Nachtigall, M.J.; Nachtigall, L.E.; Naftolin, F. The Women’s Health Initiative trial and related
studies: 10 years later: A clinician’s view. J. Steroid Biochem. Mol. Biol. 2014, 142, 4–11. [CrossRef] [PubMed]
16. Ramaa, C.S.; Shirode, A.R.; Mundada, A.S.; Kadam, V.J. Nutraceuticals—An emerging era in the treatment
and prevention of cardiovascular diseases. Curr. Pharm. Biotechnol. 2006, 7, 15–23. [CrossRef] [PubMed]
17. Aronson, J.K. Defining “nutraceuticals”: Neither nutritious nor pharmaceutical. Br. J. Clin. Pharmacol. 2017,
83, 8–19. [CrossRef] [PubMed]
18. Coppens, P.; Da Silva, M.F.; Pettman, S. European regulations on nutraceuticals, dietary supplements and
functional foods: A framework based on safety. Toxicology 2006, 221, 59–74. [CrossRef] [PubMed]
19. Watts, N.B.; Bilezikian, J.P.; Camacho, P.M.; Greenspan, S.L.; Harris, S.T.; Hodgson, S.F.; Kleerekoper, M.;
Luckey, M.M.; McClung, M.R.; Pollack, R.P.; et al. American Association of Clinical Endocrinologists
medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis.
Endocr. Pract. 2003, 9, 544–564.
20. Sullivan, S.D.; Sarrel, P.M.; Nelson, L.M. Hormone replacement therapy in young women with primary
ovarian insufficiency and early menopause. Fertil. Steril. 2016, 106, 1588–1599. [CrossRef]
21. Lethaby, A.; Ayeleke, R.O.; Roberts, H. Local oestrogen for vaginal atrophy in postmenopausal women.
Cochrane Database Syst. Rev. 2016. [CrossRef] [PubMed]
22. Torgerson, D.J.; Bell-Syer, S.E. Hormone replacement therapy and prevention of nonvertebral fractures:
A meta-analysis of randomized trials. JAMA 2001, 285, 2891–2897. [CrossRef] [PubMed]
23. Maclennan, A.H.; Broadbent, J.L.; Lester, S.; Moore, V. Oral oestrogen and combined oestrogen/progestogen
therapy versus placebo for hot flushes. Cochrane Database Syst. Rev. 2004. [CrossRef] [PubMed]
24. Writing Group for the Women’s Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin
in Healthy Postmenopausal Women: Principal Results From the Women’s Health Initiative Randomized
Controlled Trial. JAMA 2002, 288, 321–333. [CrossRef] [PubMed]
25. Tariverdian, N.; Theoharides, T.C.; Siedentopf, F.; Gutierrez, G.; Jeschke, U.; Rabinovich, G.A.; Blois, S.M.;
Arck, P.C. Neuroendocrine-immune disequilibrium and endometriosis: An interdisciplinary approach.
Semin. Immunopathol. 2007, 29, 193–210. [CrossRef] [PubMed]
26. Tit, D.M.; Bungau, S.; Iovan, C.; Cseppento, D.C.N.; Endres, L.; Sava, C.; Sabau, A.M.; Furau, G.; Furau, C.
Effects of the Hormone Replacement Therapy and of Soy Isoflavones on Bone Resorption in Postmenopause.
J. Clin. Med. 2018, 7, 297. [CrossRef] [PubMed]
27. Peng, L.; Luo, Q.; Lu, H. Efficacy and safety of bazedoxifene in postmenopausal women with osteoporosis:
A systematic review and meta-analysis. Medicine 2017, 96, e8659. [CrossRef]
28. Conjugated oestrogens/bazedoxifene for menopause. Aust. Prescr. 2017, 40, 114–115. [CrossRef]
Medicina 2019, 55, 544 11 of 17

29. LaCroix, A.Z.; Chlebowski, R.T.; Manson, J.E.; Aragaki, A.K.; Johnson, K.C.; Martin, L.; Margolis, K.L.;
Stefanick, M.L.; Brzyski, R.; Curb, J.D.; et al. Health Outcomes after Stopping Conjugated Equine Estrogens
Among Postmenopausal Women with Prior Hysterectomy. JAMA 2011, 305, 1305–1314. [CrossRef]
30. Lobo, R.A. Hormone-replacement therapy: current thinking. Nat. Rev. Endocrinol. 2017, 13, 220–231.
[CrossRef]
31. De Franciscis, P.; Mainini, G.; Messalli, E.M.; Trotta, C.; Luisi, A.; Laudando, E.; Marino, G.; Della Puca, G.;
Cerreto, F.V.; Torella, M. Arterial hypertension and female sexual dysfunction in postmenopausal women.
Clin. Exp. Obstet. Gynecol. 2013, 40, 58–60. [PubMed]
32. Johansen, N.; Liavaag, A.H.; Iversen, O.-E.; Dørum, A.; Braaten, T.; Michelsen, T.M. Use of hormone
replacement therapy after risk-reducing salpingo-oophorectomy. Acta Obstet. Gynecol. Scand. 2017, 96,
547–555. [CrossRef] [PubMed]
33. Gemmell, L.; Webster, K.; Kirtley, S.; Vincent, K.; Zondervan, K.; Becker, C. The management of menopause
in women with a history of endometriosis: A systematic review. Hum. Reprod. Updat. 2017, 23, 481–500.
[CrossRef] [PubMed]
34. Campitiello, M.R.; De Franciscis, P.; Mele, D.; Izzo, G.; Sinisi, A.; DelRio, G.; Colacurci, N. Endometrial LGR7
expression during menstrual cycle. Fertil. Steril. 2011, 95, 2511–2514. [CrossRef] [PubMed]
35. Siciliano, R.A.; Mazzeo, M.F.; Spada, V.; Facchiano, A.; D’Acierno, A.; Stocchero, M.; De Franciscis, P.;
Colacurci, N.; Sannolo, N.; Miraglia, N. Rapid peptidomic profiling of peritoneal fluid by MALDI-TOF mass
spectrometry for the identification of biomarkers of endometriosis. Gynecol. Endocrinol. 2014, 30, 872–876.
[CrossRef] [PubMed]
36. Donati, S.; Cotichini, R.; Mosconi, P.; Satolli, R.; Colombo, C.; Donati, S.; Cotichini, R.; Mosconi, P.; Satolli, R.;
Colombo, C.; et al. Menopausa e terapia ormonale: Indagine su conoscenza, atteggiamenti e comportamenti; Istituto
Superiore di Sanità: Roma, Italy, 2008; (Rapporti ISTISAN 08/28).
37. Das, L.; Bhaumik, E.; Raychaudhuri, U.; Chakraborty, R. Role of nutraceuticals in human health. J. Food
Sci. Technol. 2012, 49, 173–183. [CrossRef] [PubMed]
38. Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of The
North American Menopause Society. Menopause 2015, 22, 1155–1174. [CrossRef]
39. Gambacciani, M.; Cagnacci, A.; Lello, S. Hormone replacement therapy and prevention of chronic conditions.
Climacteric 2019, 22, 303–306. [CrossRef]
40. Mosconi, P.; Donati, S.; Colombo, C.; Mele, A.; Liberati, A.; Satolli, R. Informing women about hormone
replacement therapy: The consensus conference statement. BMC Women Health 2009, 9, 14. [CrossRef]
41. Nicoletti, M. Nutraceuticals and botanicals: Overview and perspectives. Int. J. Food Sci. Nutr. 2012, 63, 2–6.
[CrossRef]
42. Santini, A.; Cammarata, S.M.; Capone, G.; Ianaro, A.; Tenore, G.C.; Pani, L.; Novellino, E. Nutraceuticals:
Opening the debate for a regulatory framework. Br. J. Clin. Pharmacol. 2018, 84, 659–672. [CrossRef]
[PubMed]
43. Brower, V. A nutraceutical a day may keep the doctor away. EMBO Rep. 2005, 6, 708–711. [CrossRef]
[PubMed]
44. Donati, S.; Cotichini, R.; Mosconi, P.; Satolli, R.; Colombo, C.; Liberati, A.; Mele, E.A. Menopause: Knowledge,
attitude and practice among Italian women. Maturitas 2009, 63, 246–252. [CrossRef] [PubMed]
45. Laganà, A.S.; Vitale, S.G.; Stojanovska, L.; Lambrinoudaki, I.; Apostolopoulos, V.; Chiofalo, B.; Rizzo, L.;
Basile, F. Preliminary results of a single-arm pilot study to assess the safety and efficacy of visnadine,
prenylflavonoids and bovine colostrum in postmenopausal sexually active women affected by vulvovaginal
atrophy. Maturitas 2018, 109, 78–80. [CrossRef] [PubMed]
46. Pinkerton, J.V.; Santen, R.J. Managing vasomotor symptoms in women after cancer. Climacteric 2019.
[CrossRef] [PubMed]
47. Gulati, O.P.; Ottaway, P.B. Legislation relating to nutraceuticals in the European Union with a particular
focus on botanical-sourced products. Toxicology 2006, 221, 75–87. [CrossRef] [PubMed]
48. Lobstein, T.; Davies, S. Defining and labelling ‘healthy’ and ‘unhealthy’ food. Public Health Nutr. 2008, 12,
331–340. [CrossRef]
49. De Felice, S. The Nutraceutical Evolution: Fueling a Powerful, New International Market. The Foundation for
Innovation in Medicine: 1989. Available online: https://fimdefelice.org/library/the-nutraceutical-revolution-
fueling-a-powerful-new-international-market/ (accessed on 20 June 2019).
Medicina 2019, 55, 544 12 of 17

50. Takase, H.; Imanishi, K.; Miura, O.; Yumioka, E. A possible mechanism for the gastric mucosal protection by
Oren-gedoku-to(OGT), a traditional herbal medicine. Jpn. J. Pharmacol. 1989, 51, 17–23. [CrossRef]
51. Kobayashi, Y. Kampo Medicine in the New Model Core Curriculum of Pharmaceutical Education. Yakugaku
Zasshi 2016, 136, 423–432. [CrossRef]
52. Ushiroyama, T. The role of traditional Japanese medicine (Kampo) in the practice of psychosomatic medicine:
The usefulness of Kampo in the treatment of the stress-related symptoms of women, especially those with
peri-menopausal disorder. Biopsychosoc. Med. 2013, 7, 16. [CrossRef]
53. Tonob, D.; Melby, M.K. Broadening our perspectives on complementary and alternative medicine for
menopause: A narrative review. Maturitas 2017, 99, 79–85. [CrossRef]
54. Kargozar, R.; Azizi, H.; Salari, R. A review of effective herbal medicines in controlling menopausal symptoms.
Electron. Physician 2017, 9, 5826–5833. [CrossRef] [PubMed]
55. Yu, Q. Traditional Chinese medicine: Perspectives on and treatment of menopausal symptoms. Climacteric
2018, 21, 93–95. [CrossRef] [PubMed]
56. Taylor-Swanson, L.; Thomas, A.; Ismail, R.; Schnall, J.G.; Cray, L.; Mitchell, E.S.; Woods, N.F. Effects of
traditional Chinese medicine on symptom clusters during the menopausal transition. Climacteric 2015, 18,
142–156. [CrossRef] [PubMed]
57. Furukawa, M.; Sakashita, H.; Kamide, M.; Umeda, R. Inhibitory Effects of Kampo Medicine on Epstein-Barr
Virus Antigen Induction by Tumor Promoter. Auris Nasus Larynx 1990, 17, 49–54. [CrossRef]
58. Elkind-Hirsch, K. Effect of dietary phytoestrogens on hot flushes: Can soy-based proteins substitute for
traditional estrogen replacement therapy? Menopause 2001, 8, 154–156. [CrossRef]
59. Jampilek, J.; Kos, J.; Kralova, K. Potential of Nanomaterial Applications in Dietary Supplements and Foods
for Special Medical Purposes. Nanomaterials 2019, 9, 296. [CrossRef]
60. Simonelli, A.; Guadagni, R.; De Franciscis, P.; Colacurci, N.; Pieri, M.; Basilicata, P.; Pedata, P.; Lamberti, M.;
Sannolo, N.; Miraglia, N. Environmental and occupational exposure to bisphenol A and endometriosis:
Urinary and peritoneal fluid concentration levels. Int. Arch. Occup. Environ. Health 2017, 90, 49–61.
[CrossRef]
61. Newton, K.M.; Reed, S.D.; Lacroix, A.Z.; Grothaus, L.C.; Ehrlich, K.; Guiltinan, J. Treatment of Vasomotor
Symptoms of Menopause with Black Cohosh, Multibotanicals, Soy, Hormone Therapy, or Placebo.
Ann. Intern. Med. 2006, 145, 869. [CrossRef]
62. Fait, T. Menopause hormone therapy: Latest developments and clinical practice. Drugs Context 2019, 8, 1–9.
[CrossRef]
63. Thomas, A.J.; Ismail, R.; Taylor-Swanson, L.; Cray, L.; Schnall, J.G.; Mitchell, E.S.; Woods, N.F. Effects of
isoflavones and amino acid therapies for hot flashes and co-occurring symptoms during the menopausal
transition and early postmenopause: A systematic review. Maturitas 2014, 78, 263–276. [CrossRef] [PubMed]
64. Roberts, H.; Lethaby, A. Phytoestrogens for menopausal vasomotor symptoms: A Cochrane review summary.
Maturitas 2014, 78, 79–81. [CrossRef] [PubMed]
65. Nettleton, J.A.; Greany, K.A.; Thomas, W.; Wangen, K.E.; Adlercreutz, H.; Kurzer, M.S. The effect of soy
consumption on the urinary 2:16-hydroxyestrone ratio in postmenopausal women depends on equol
production status but is not influenced by probiotic consumption. J. Nutr. 2005, 135, 603–608. [CrossRef]
[PubMed]
66. Torella, M.; Del Deo, F.; Grimaldi, A.; Iervolino, S.; Pezzella, M.; Tammaro, C.; Gallo, P.; Rappa, C.; De
Franciscis, P.; Colacurci, N. Efficacy of an orally administered combination of hyaluronic acid, chondroitin
sulfate, curcumin and quercetin for the prevention of recurrent urinary tract infections in postmenopausal
women. Eur. J. Obstet. Gynecol. Reprod. Biol. 2016, 207, 125–128. [CrossRef] [PubMed]
67. Chien, H.-L.; Huang, H.-Y.; Chou, C.-C. Transformation of isoflavone phytoestrogens during the fermentation
of soymilk with lactic acid bacteria and bifidobacteria. Food Microbiol. 2006, 23, 772–778. [CrossRef] [PubMed]
68. Ding, W.; Shah, N. Enhancing the Biotransformation of Isoflavones in Soymilk Supplemented with Lactose
Using Probiotic Bacteria during Extended Fermentation. J. Food Sci. 2010, 75, M140–M149. [CrossRef]
[PubMed]
69. Ribeiro, A.E.; De Moraes, A.V.G.; Costa-Paiva, L.H.; Pedro, A.O.; Monteiro, N.E.S. Can the use of probiotics
in association with isoflavone improve the symptoms of genitourinary syndrome of menopause? Results
from a randomized controlled trial. Menopause 2019, 26, 643–652. [CrossRef] [PubMed]
Medicina 2019, 55, 544 13 of 17

70. Roozbeh, N.; Kashef, R.; Ghazanfarpour, M.; Kargarfard, L.; Darvish, L.; Khadivzadeh, T.; Dizavandi, F.R.;
Afiat, M. Overview of the Effect of Herbal Medicines and Isoflavones on the Treatment of Cognitive Function.
J. Menopausal Med. 2018, 24, 113–118. [CrossRef]
71. Dizavandi, F.R.; Ghazanfarpour, M.; Roozbeh, N.; Kargarfard, L.; Khadivzadeh, T.; Dashti, S. An overview
of the phytoestrogen effect on vaginal health and dyspareunia in peri- and post-menopausal women.
Post Reprod. Health 2019, 25, 11–20. [CrossRef]
72. Munro, I.C.; Harwood, M.; Hlywka, J.J.; Stephen, A.M.; Doull, J.; Flamm, W.G.; Adlercreutz, H. Soy
Isoflavones: A Safety Review. Nutr. Rev. 2003, 61, 1–33. [CrossRef]
73. Kheirkhah, M.; Naieri, S.; Tabari, N. The effect of herbal tea capsule on menopause hot flashes. J. Fam. Med.
Prim. Care 2018, 7, 1074–1078.
74. De Smet, P.A. Is there any danger in using traditional remedies? J. Ethnopharmacol. 1991, 32, 43–50. [CrossRef]
75. Sheehan, D.M. Herbal Medicines, Phytoestrogens and Toxicity: Risk: Benefit Considerations. Exp. Biol. Med.
1998, 217, 379–385. [CrossRef] [PubMed]
76. Drewe, J.; A Bucher, K.; Zahner, C. A systematic review of non-hormonal treatments of vasomotor symptoms
in climacteric and cancer patients. SpringerPlus 2015, 4, 65. [CrossRef] [PubMed]
77. Xi, S.; Liske, E.; Wang, S.; Liu, J.; Zhang, Z.; Geng, L.; Hu, L.; Jiao, C.; Zheng, S.; Zepelin, H.H.; et al. Effect of
Isopropanolic Cimicifuga racemosa Extract on Uterine Fibroids in Comparison with Tibolone among Patients
of a Recent Randomized, Double Blind, Parallel-Controlled Study in Chinese Women with Menopausal
Symptoms. Evid. Based Complement. Altern. Med. 2014, 2014, 717686. [CrossRef]
78. Leach, M.J.; Moore, V. Black cohosh (Cimicifuga spp.) for menopausal symptoms. Cochrane Database Syst. Rev.
2012. [CrossRef] [PubMed]
79. Chenoy, R.; Hussain, S.; Tayob, Y.; O’Brien, P.M.S.; Moss, M.Y.; Morse, P.F. Effect of oral gamolenic acid from
evening primrose oil on menopausal flushing. BMJ 1994, 308, 501–503. [CrossRef]
80. Farzaneh, F.; Fatehi, S.; Sohrabi, M.-R.; Alizadeh, K. The effect of oral evening primrose oil on menopausal
hot flashes: A randomized clinical trial. Arch. Gynecol. Obstet. 2013, 288, 1075–1079. [CrossRef]
81. Ghazanfarpour, M.; Mohammadzadeh, F.; Shokrollahi, P.; Khadivzadeh, T.; Najaf Najafi, M.; Hajirezaee, H.;
Afiat, M. Effect of Foeniculum vulgare (fennel) on symptoms of depression and anxiety in postmenopausal
women: A double-blind randomised controlled trial. J. Obstet. Gynaecol. 2018, 38, 121–126. [CrossRef]
82. Javidnia, K.; Dastgheib, L.; Samani, S.M.; Nasiri, A. Antihirsutism activity of Fennel (fruits of Foeniculum
vulgare) extract—A double-blind placebo controlled study. Phytomedicine 2003, 10, 455–458. [CrossRef]
83. Yavangi, M.; Rabiee, S.; Nazari, S.; Farimani-Sanoee, M.; Amiri, I.; Bahmanzadeh, M.; Heidari-Soureshjani, S.
Comparison of the Effect of Oestrogen Plus Foeniculum vulgare Seed and Oestrogen alone on Increase in
Endometrial Thickness in Infertile Women. J. Clin. Diagn. Res. 2018, 12, QC01–QC04. [CrossRef]
84. Elsabagh, S.; Hartley, D.E.; File, S.E. Limited cognitive benefits in Stage +2 postmenopausal women after 6
weeks of treatment with Ginkgo biloba. J. Psychopharmacol. 2005, 19, 173–181. [CrossRef] [PubMed]
85. Pebdani, M.A.; Taavoni, S.; Seyedfatemi, N.; Haghani, H. Triple-blind, placebo-controlled trial of Ginkgo
biloba extract on sexual desire in postmenopausal women in Tehran. Iran. J. Nurs. Midwifery Res. 2014, 19,
262–265. [PubMed]
86. Menati, L.; Khaleghinezhad, K.; Tadayon, M.; Siahpoosh, A. Evaluation of Contextual and Demographic
Factors on Licorice Effects on Reducing Hot Flashes in Postmenopause Women. Health Care Women Int. 2014,
35, 87–99. [CrossRef] [PubMed]
87. Farese, R.V.; Biglieri, E.G.; Shackleton, C.H.L.; Irony, I.; Gomez-Fontes, R. Licorice-Induced
Hypermineralocorticoidism. N. Engl. J. Med. 1991, 325, 1223–1227. [CrossRef]
88. Ghazanfarpour, M.; Sadeghi, R.; Latifnejad Roudsari, R.; Khadivzadeh, T.; Khorsand, I.; Afiat, M.;
Esmaeilizadeh, M. Effects of flaxseed and Hypericum perforatum on hot flash, vaginal atrophy and
estrogen-dependent cancers in menopausal women: A systematic review and meta-analysis. Avicenna J.
Phytomed. 2016, 6, 273–283. [PubMed]
89. You, M.-K.; Kim, H.-J.; Kook, J.H.; Kim, H.-A., St. John’s Wort Regulates Proliferation and Apoptosis in
MCF-7 Human Breast Cancer Cells by Inhibiting AMPK/mTOR and Activating the Mitochondrial Pathway.
Int. J. Mol. Sci. 2018, 19, 966. [CrossRef]
90. Laakmann, E.; Grajecki, D.; Doege, K.; Zu Eulenburg, C.; Bühling, K.J. Efficacy of Cimicifuga racemosa,
Hypericum perforatum and Agnus castus in the treatment of climacteric complaints: A systematic review.
Gynecol. Endocrinol. 2012, 28, 703–709. [CrossRef]
Medicina 2019, 55, 544 14 of 17

91. Liu, Y.-R.; Jiang, Y.-L.; Huang, R.-Q.; Yang, J.-Y.; Xiao, B.-K.; Dong, J.-X. Hypericum perforatum L. preparations
for menopause: A meta-analysis of efficacy and safety. Climacteric 2014, 17, 325–335. [CrossRef]
92. Zhang, C.; Li, Z.; Zhang, C.-Y.; Li, M.; Lee, Y.; Zhang, G.-G. Extract Methods, Molecular Characteristics, and
Bioactivities of Polysaccharide from Alfalfa (Medicago sativa L.). Nutrients 2019, 11, 1181. [CrossRef]
93. De Leo, V.; Lanzetta, D.; Cazzavacca, R.; Morgante, G. Treatment of neurovegetative menopausal symptoms
with a phytotherapeutic agent. Minerva Ginecol. 1998, 50, 207–211. [PubMed]
94. Klerks, M.M.; Van Gent-Pelzer, M.; Franz, E.; Zijlstra, C.; Van Bruggen, A.H.C. Physiological and Molecular
Responses of Lactuca sativa to Colonization by Salmonella enterica Serovar Dublin. Appl. Environ. Microbiol.
2007, 73, 4905–4914. [CrossRef] [PubMed]
95. Kim, S.A.; Kim, O.M.; Rhee, M.S. Changes in microbial contamination levels and prevalence of foodborne
pathogens in alfalfa (Medicago sativa) and rapeseed (Brassica napus) during sprout production in manufacturing
plants. Lett. Appl. Microbiol. 2013, 56, 30–36. [CrossRef] [PubMed]
96. Rasmussen, P. Lemon balm—Melissa officinalis; also known as lemon balm, bee balm, garden balm, Melissa,
melissengeist. J. Prim. Health Care 2011, 3, 165–166. [CrossRef] [PubMed]
97. Shakeri, A.; Sahebkar, A.; Javadi, B. Melissa officinalis L.—A review of its traditional uses, phytochemistry
and pharmacology. J. Ethnopharmacol. 2016, 188, 204–228. [CrossRef] [PubMed]
98. Nasri, H.; Rafieian-Kopaei, M. Oxidative Stress and Aging Prevention. Int. J. Prev. Med. 2013, 4, 1101–1102.
[PubMed]
99. Miraj, S.; Rafieian, K.; Kiani, S. Melissa officinalis L: A Review Study with an Antioxidant Prospective. J. Evid.
Based Complementary Altern. Med. 2017, 22, 385–394. [CrossRef] [PubMed]
100. Gurčík, L’.; Dúbravská, R.; Miklovičová, J. Economics of the cultivation of Salvia officinalis and Melissa
officinalis. Agric. Econ. 2012, 51, 348–356. [CrossRef]
101. Pérez-Sánchez, A.; Barrajón-Catalán, E.; Herranz-López, M.; Castillo, J.; Micol, V. Lemon balm extract (Melissa
officinalis, L.) promotes melanogenesis and prevents UVB-induced oxidative stress and DNA damage in a
skin cell model. J. Dermatol. Sci. 2016, 84, 169–177. [CrossRef]
102. Shergis, J.L.; Zhang, A.L.; Zhou, W.; Xue, C.C. Panax ginseng in Randomised Controlled Trials: A Systematic
Review. Phyther. Res. 2013, 27, 949–965. [CrossRef]
103. Lee, K.J.; Ji, G.E. The effect of fermented red ginseng on depression is mediated by lipids. Nutr. Neurosci.
2014, 17, 7–15. [CrossRef]
104. Leung, K.W.; Cheung, L.W.T.; Pon, Y.L.; Wong, R.N.S.; Mak, N.K.; Fan, T.-P.; Au, S.C.L.; Tombran-Tink, J.;
Wong, A.S.T. Ginsenoside Rb1 inhibits tube-like structure formation of endothelial cells by regulating
pigment epithelium-derived factor through the oestrogen β receptor. Br. J. Pharmacol. 2007, 152, 207–215.
[CrossRef] [PubMed]
105. Cho, J.; Park, W.; Lee, S.; Ahn, W.; Lee, Y. Ginsenoside-Rb1 from Panax ginseng C.A. Meyer Activates
Estrogen Receptor-α and -β, Independent of Ligand Binding. J. Clin. Endocrinol. Metab. 2004, 89, 3510–3515.
[CrossRef] [PubMed]
106. Lee, H.W.; Choi, J.; Lee, Y.; Kil, K.-J.; Lee, M.S. Ginseng for managing menopausal woman’s health. Medicine
2016, 95, e4914. [CrossRef]
107. Miroddi, M.; Calapai, G.; Navarra, M.; Minciullo, P.; Gangemi, S. Passiflora incarnata L.: Ethnopharmacology,
clinical application, safety and evaluation of clinical trials. J. Ethnopharmacol. 2013, 150, 791–804. [CrossRef]
108. Fahami, F.; Asali, Z.; Aslani, A.; Fathizadeh, N. A comparative study on the effects of Hypericum Perforatum
and passion flower on the menopausal symptoms of women referring to Isfahan city health care centers.
Iran. J. Nurs. Midwifery Res. 2010, 15, 202–207. [PubMed]
109. Kim, M.; Lim, H.-S.; Lee, H.-H.; Kim, T.-H. Role Identification of Passiflora Incarnata Linnaeus: A Mini
Review. J. Menopausal. Med. 2017, 23, 156–159. [CrossRef]
110. Mosavat, S.H.; Jaberi, A.R.; Sobhani, Z.; Mosaffa-Jahromi, M.; Iraji, A.; Moayedfard, A. Efficacy of Anise
(Pimpinella anisum L.) oil for migraine headache: A pilot randomized placebo-controlled clinical trial.
J. Ethnopharmacol. 2019, 236, 155–160. [CrossRef]
111. Nahidi, F.; Kariman, N.; Simbar, M.; Mojab, F. The Study on the Effects of Pimpinella anisum on Relief and
Recurrence of Menopausal Hot Flashes. Iran. J. Pharm. Res. 2012, 11, 1079–1085.
112. Al Mofleh, I.A. Aqueous suspension of anise “Pimpinella anisum” protects rats against chemically induced
gastric ulcers. World J. Gastroenterol. 2007, 13, 1112–1118. [CrossRef]
Medicina 2019, 55, 544 15 of 17

113. Pontes, V.C.B.; Rodrigues, D.P.; Caetano, A.; Gamberini, M.T.; Rodriguesa, D.P. Preclinical investigation of
the cardiovascular actions induced by aqueous extract of Pimpinella anisum L. seeds in rats. J. Ethnopharmacol.
2019, 237, 74–80. [CrossRef] [PubMed]
114. Tober, C.; Schoop, R. Modulation of neurological pathways by Salvia officinalis and its dependence on
manufacturing process and plant parts used. BMC Complement. Altern. Med. 2019, 19, 128. [CrossRef]
115. Perry, N.; Houghton, P.; Jenner, P.; Keith, A.; Perry, E. Salvia lavandulaefolia essential oil inhibits cholinesterase
in vivo. Phytomedicine 2002, 9, 48–51. [CrossRef] [PubMed]
116. Pereira, O.R.; Catarino, M.D.; Afonso, A.F.; Silva, A.M.S.; Cardoso, S.M. Salvia elegans, Salvia greggii and Salvia
officinalis Decoctions: Antioxidant Activities and Inhibition of Carbohydrate and Lipid Metabolic Enzymes.
Molecules 2018, 23, 3169. [CrossRef]
117. Myers, S.; Vigar, V. Effects of a standardised extract of Trifolium pratense (Promensil) at a dosage of 80mg in
the treatment of menopausal hot flushes: A systematic review and meta-analysis. Phytomedicine 2017, 24,
141–147. [CrossRef] [PubMed]
118. Lee, S.A.; Moon, S.-M.; Han, S.H.; Kim, J.-S.; Kim, D.K.; Kim, C.S. The Effect of the Prethanol Extract of Trifolium
pratense Leaves on Interleukin-1β-Induced Cartilage Matrix Degradation in Primary Rat Chondrocytes.
Cells Tissues Organs 2018, 206, 95–105. [CrossRef] [PubMed]
119. Ghazanfarpour, M.; Sadeghi, R.; Roudsari, R.L.; Khorsand, I.; Khadivzadeh, T.; Muoio, B. Red clover for
treatment of hot flashes and menopausal symptoms: A systematic review and meta-analysis. J. Obstet.
Gynaecol. 2016, 36, 301–311. [CrossRef]
120. Thompson Coon, J.; Pittler, M.H.; Ernst, E. Trifolium pratense isoflavones in the treatment of menopausal hot
flushes: A systematic review and meta-analysis. Phytomedicine 2007, 14, 153–159. [CrossRef]
121. Anjaneyulu, K.; Bhat, K.M.; Srinivasa, S.R.; Devkar, R.A.; Henry, T. Beneficial Role of Hydro-alcoholic Seed
Extract of Trigonella foenum graecum on Bone Structure and Strength in Menopause Induced Osteopenia.
Ethiop. J. Health Sci. 2018, 28, 787–794. [PubMed]
122. Steels, E.; Steele, M.L.; Harold, M.; Coulson, S. Efficacy of a Proprietary Trigonella foenum-graecum L.
De-Husked Seed Extract in Reducing Menopausal Symptoms in Otherwise Healthy Women: A Double-Blind,
Randomized, Placebo-Controlled Study. Phyther. Res. 2017, 31, 1316–1322. [CrossRef] [PubMed]
123. Mineo, L.; Concerto, C.; Mayorga, T.; Paula, M.; Chusid, E.; Patel, D.; Aguglia, E.; Battaglia, F. Valeriana
officinalis Root Extract Modulates Cortical Excitatory Circuits in Humans. Neuropsychobiology 2017, 75, 46–51.
[CrossRef]
124. Occhiuto, F.; Pino, A.; Palumbo, D.R.; Samperi, S.; De Pasquale, R.; Sturlese, E.; Circosta, C.; Pasquale, R.
Relaxing effects of Valeriana officinalis extracts on isolated human non-pregnant uterine muscle. J. Pharm.
Pharmacol. 2009, 61, 251–256. [CrossRef]
125. Jenabi, E.; Shobeiri, F.; Hazavehei, S.M.M.; Roshanaei, G. The effect of Valerian on the severity and frequency
of hot flashes: A triple-blind randomized clinical trial. Women Health 2018, 58, 297–304. [CrossRef] [PubMed]
126. Schellenberg, R. Treatment for the premenstrual syndrome with agnus castus fruit extract: Prospective,
randomised, placebo controlled study. BMJ 2001, 322, 134–137. [CrossRef] [PubMed]
127. Dugoua, J.-J.; Seely, D.; Perri, D.; Koren, G.; Mills, E. Safety and efficacy of chastetree (Vitex agnus-castus)
during pregnancy and lactation. Can. J. Clin. Pharmacol. 2008, 15, e74–e79.
128. De Franciscis, P.; Grauso, F.; Luisi, A.; Schettino, M.; Torella, M.; Colacurci, N. Adding Agnus Castus
and Magnolia to Soy Isoflavones Relieves Sleep Disturbances Besides Postmenopausal Vasomotor
Symptoms-Long Term Safety and Effectiveness. Nutrients 2017, 9, 129. [CrossRef] [PubMed]
129. Zollman, C.; Vickers, A. ABC of complementary medicine: Complementary medicine in conventional
practice. BMJ 1999, 319, 901–904. [CrossRef]
130. Vashisht, A.; Domoney, C.L.; Cronje, W.; Studd, J.W.W. Prevalence of and satisfaction with complementary
therapies and hormone replacement therapy in a specialist menopause clinic. Climacteric 2001, 4, 250–256.
[CrossRef]
131. Parazzini, F. Resveratrol, tryptophanum, glycine and vitamin E: A nutraceutical approach to sleep disturbance
and irritability in peri- and post-menopause. Minerva Ginecol. 2015, 67, 1–5. [PubMed]
132. Golmakani, N.; Parnan Emamverdikhan, A.; Zarifian, A.; Sajadi Tabassi, S.A.; Hassanzadeh, M. Vitamin
E as alternative local treatment in genitourinary syndrome of menopause: A randomized controlled trial.
Int. Urogynecol. J. 2019, 30, 831–837. [CrossRef] [PubMed]
Medicina 2019, 55, 544 16 of 17

133. Laganà, A.S.; Vitale, S.G.; Ban Frangež, H.; Vrtačnik-Bokal, E.; D’Anna, R. Vitamin D in human reproduction:
The more, the better? An evidence-based critical appraisal. Eur. Rev. Med. Pharmacol. Sci. 2017, 21, 4243–4251.
[PubMed]
134. Colacurci, N.; Caprio, F.; La Verde, E.; Trotta, C.; Ianniello, R.; Mele, D.; De Franciscis, P. Sequential protocol
with urinary-FSH/recombinant-FSH versus standard protocol with recombinant-FSH in women of advanced
age undergoing IVF. Gynecol. Endocrinol. 2014, 30, 730–733. [CrossRef] [PubMed]
135. Paul, C.; Laganà, A.S.; Maniglio, P.; Triolo, O.; Brady, D.M. Inositol’s and other nutraceuticals’ synergistic
actions counteract insulin resistance in polycystic ovarian syndrome and metabolic syndrome: State-of-the-art
and future perspectives. Gynecol. Endocrinol. 2016, 32, 431–438. [CrossRef] [PubMed]
136. Ferreira, P.P.; Cangussu, L.; Bueloni-Dias, F.N.; Orsatti, C.L.; Schmitt, E.B.; Nahas-Neto, J.; Nahas, E.A.P.
Vitamin D supplementation improves the metabolic syndrome risk profile in postmenopausal women.
Climacteric 2019. [CrossRef] [PubMed]
137. Colonese, F.; Laganà, A.S.; Colonese, E.; Sofo, V.; Salmeri, F.M.; Granese, R.; Triolo, O. The Pleiotropic Effects
of Vitamin D in Gynaecological and Obstetric Diseases: An Overview on a Hot Topic. BioMed Res. Int. 2015,
2015, 986281. [CrossRef]
138. Rizzo, G.; Laganà, A.; Rapisarda, A.; La Ferrera, G.; Buscema, M.; Rossetti, P.; Nigro, A.; Muscia, V.; Valenti, G.;
Sapia, F.; et al. Vitamin B12 among Vegetarians: Status, Assessment and Supplementation. Nutrients 2016, 8,
767. [CrossRef] [PubMed]
139. McCabe, D.; Lisy, K.; Lockwood, C.; Colbeck, M. The impact of essential fatty acid, B vitamins, vitamin C,
magnesium and zinc supplementation on stress levels in women: A systematic review. JBI Database Syst.
Rev. Implement. Rep. 2017, 15, 402–453.
140. Sandoval-Ramírez, B.A.; Lamuela-Raventós, R.; Estruch, R.; Sasot, G.; Doménech, M.; Tresserra-Rimbau, A.
Beer Polyphenols and Menopause: Effects and Mechanisms—A Review of Current Knowledge. Oxid. Med.
Cell. Longev. 2017, 2017, 4749131. [CrossRef]
141. Terauchi, M.; Horiguchi, N.; Kajiyama, A.; Akiyoshi, M.; Owa, Y.; Kato, K.; Kubota, T. Effects of grape seed
proanthocyanidin extract on menopausal symptoms, body composition, and cardiovascular parameters
in middle-aged women: A randomized, double-blind, placebo-controlled pilot study. Menopause 2014, 21,
990–996. [CrossRef]
142. Corzo, L.; Rodriguez, S.; Alejo, R.; Fernandez-Novoa, L.; Aliev, G.; Cacabelos, R. E-MHK-0103 (MineraxinTM ):
A Novel Nutraceutical with Biological Properties in Menopausal Conditions. Curr. Drug. Metab. 2017, 18,
39–49. [CrossRef]
143. Erkkola, R.; Vervarcke, S.; Vansteelandt, S.; Rompotti, P.; De Keukeleire, D.; Heyerick, A. A randomized,
double-blind, placebo-controlled, cross-over pilot study on the use of a standardized hop extract to alleviate
menopausal discomforts. Phytomedicine 2010, 17, 389–396. [CrossRef] [PubMed]
144. Arranz, S.; Chiva-Blanch, G.; Valderas-Martínez, P.; Medina-Remón, A.; Lamuela-Raventos, R.M.; Estruch, R.
Wine, Beer, Alcohol and Polyphenols on Cardiovascular Disease and Cancer. Nutrients 2012, 4, 759–781.
[CrossRef] [PubMed]
145. Gresele, P.; Cerletti, C.; Guglielmini, G.; Pignatelli, P.; De Gaetano, G.; Violi, F. Effects of resveratrol and other
wine polyphenols on vascular function: An update. J. Nutr. Biochem. 2011, 22, 201–211. [CrossRef] [PubMed]
146. Villa, P.; Amar, I.D.; Bottoni, C.; Cipolla, C.; Dinoi, G.; Moruzzi, M.C.; Scambia, G.; Lanzone, A. The impact of
combined nutraceutical supplementation on quality of life and metabolic changes during the menopausal
transition: A pilot randomized trial. Arch. Gynecol. Obstet. 2017, 296, 791–801. [CrossRef] [PubMed]
147. Wong, R.H.; Evans, H.M.; Howe, P.R. Resveratrol supplementation reduces pain experience by
postmenopausal women. Menopause 2017, 24, 916–922. [CrossRef] [PubMed]
148. Giolo, J.S.; Costa, J.G.; Da Cunha-Junior, J.P.; Pajuaba, A.C.A.M.; Taketomi, E.A.; De Souza, A.V.; Caixeta, D.C.;
Peixoto, L.G.; De Oliveira, E.P.; Everman, S.; et al. The Effects of Isoflavone Supplementation Plus Combined
Exercise on Lipid Levels, and Inflammatory and Oxidative Stress Markers in Postmenopausal Women.
Nutrients 2018, 10, 424. [CrossRef] [PubMed]
149. Purdue-Smithe, A.C.; Whitcomb, B.W.; Szegda, K.L.; Boutot, M.E.; Manson, J.E.; Hankinson, S.E.; Rosner, B.A.;
Troy, L.M.; Michels, K.B.; Bertone-Johnson, E.R. Vitamin D and calcium intake and risk of early menopause12.
Am. J. Clin. Nutr. 2017, 105, 1493–1501.
Medicina 2019, 55, 544 17 of 17

150. Mintziori, G.; Lambrinoudaki, I.; Goulis, D.G.; Ceausu, I.; Depypere, H.; Erel, C.T.; Pérez-López, F.R.;
Schenck-Gustafsson, K.; Simoncini, T.; Trémollières, F.; et al. EMAS position statement: Non-hormonal
management of menopausal vasomotor symptoms. Maturitas 2015, 81, 410–413. [CrossRef]
151. Woyka, J. Consensus statement for non-hormonal-based treatments for menopausal symptoms. Post Reprod.
Health 2017, 23, 71–75. [CrossRef]
152. Nelson, H.D.; Vesco, K.K.; Haney, E.; Fu, R.; Nedrow, A.; Miller, J.; Nicolaidis, C.; Walker, M.; Humphrey, L.
Nonhormonal therapies for menopausal hot flashes: Systematic review and meta-analysis. JAMA 2006, 295,
2057–2071. [CrossRef]
153. Sassarini, J.; Lumsden, M.A. Non-hormonal management of vasomotor symptoms. Climacteric 2013, 16,
31–36. [CrossRef] [PubMed]

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