AFRAGIL IN THE TREATMENT OF 34 MENOPAUSE SYMPTOMS: A PILOT STUDY - VOLUME 52
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V O L U M E 5 2 · S U P P L. 1 T O No. 2 · J U N E 2 0 1 0
AFRAGIL® IN THE TREATMENT
OF 34 MENOPAUSE SYMPTOMS:
A PILOT STUDY
G. BELCARO, M. R. CESARONE, U. CORNELLI, M. DUGALLPANMINERVA MEDICA
Quarterly Review of European Medicine
Official Journal of the Italian Medical Association
Official Journal of “Europa Medica”
Chief-Editor
Maria Luisa BENZO
Associate Editor
Rinaldo PELLICANO
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Luigi ALLEGRA, Milan, Italy Mario CONDORELLI, Naples, Italy Giovanni MELIOLI, Genoa, Italy
Alberto ANGELI, Turin, Italy Giovanni CORRAO, Milan, Italy Philip MORTIMER, London, UK
John G. BARTLETT, Baltimore, USA Antonio CRAXI, Palermo, Italy Antonio MUSSA, Turin, Italy
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Quarterly publication. Authorized by Turin Court no. 1279 of December
27, 1958
Graphic design of the cover: Eleonora GarosciPANMINERVA MED 2010;52(Suppl. 1 to No. 2):1-6
Afragil® in the treatment of 34 menopause symptoms:
a pilot study
G. BELCARO 1, M. R. CESARONE 1, U. CORNELLI 2, M. DUGALL 1
Aim. A combination of calcium, vitamin D3, lycopene , astax- 1Irvine3 Circulation/Vascular Labs
antin and Citrus bioflavoid (MF Afragil®) was administered Department of Biomedical Sciences
for a period of 8 weeks to 65 women to determine its effects in University of Chieti-Pescara
reducing signs/symptoms of climacteric status. San Valentino Vascular Screening Project, Chieti, Italy
Methods. Two groups of women were compared in a registry 2Loyola University School of Medicine, Chicago, IL, USA
study (33 treated with MF Afragil® and 32 with no treatment).
The climacteric condition was determined by using the 34-
symptom questionnaire MSSQ, which was filled out at inclu-
sion in the trial and after 8 weeks of treatment. The MSSQ
signs/symptoms scores (Common Symptoms, Changes and year after the final menstrual period. However, shortly
Pains) of the two groups were comparable at inclusion, where- before that point, when clinical features begin, a
as after 8 weeks a significant reduction of many variables was menopausal transition period known as perimenopause
found in the group treated with MF Afragil® and in the control takes place. This period, which continues during the
group.
year following menopause and ends with the menopausal
Results. Following the treatment with MF Afragil®, the total
MSSQ score was reduced by more than 45%. There was a sig- phases, is defined as climacteric status.
nificant reduction in hot flashes, CNS symptoms (depression, The primary symptoms of perimenopause are char-
anxiety and panic disorders), incontinence and joint pain, acterized by vasomotor symptoms (e.g., hot flashes,
which are among the most frequent symptoms of climacteric sta- night sweats), menstrual changes (e.g., oligomenorrhea,
tus. Otsteoporosis was not analyzed due to the short period of amenorrhea), vaginal dryness, and painful intercourse
treatment. (dyspareunia). However, there are many other sec-
Conclusion. MF Afragil® was found to be efficient in reducing ondary symptoms such as urinary incontinence, mood
climacteric symptoms following a short-term administration.
changes and somatic complaints that are also frequent
More prolonged treatment and more cases are under analysis
to also determine its effect on osteroporosis. and may have an impact on the quality of life.
Therapies directed at primary and secondary symp-
KEY WORDS: Menopause - Calcium - Antioxidants - Climacteric. toms include treatment with estrogen either by itself or
with progestins, androgens, bioidentical hormones,
and also antidepressants, phytoestrogens and botani-
cals. According to a Cochran review, oral hormone
M enopause, the permanent cessation of menstrua-
tion due to the loss of ovarian and follicular activ-
ity, is the major event in the aging process for women in
therapy is highly effective in the control of vasomotor
symptoms,1 which are the major complaints of
their early 1950s. Many women spend almost one third menopausal transition. However, the use of hormone
of their lives in menopause. Menopause is diagnosed one therapy has declined since the results of the Women’s
Health Initiative studies,2, 3 which found a more pro-
nounced risk of thromboembolism, stroke and breast
Corresponding author: G. Belcaro, MD, PhD, Irvine3 Circulation/
Vascular Labs, Chieti-Pescara University, SS 16bis, 94 (A), Spoltore, cancer using these products, despite a reduction of hip
65100 Pescara, Italy. E-mail: cardres@abol.it fractures and colorectal cancer.
Vol. 52 - Suppl. 1 to No. 2 PANMINERVA MEDICA 1BELCARO AFRAGIL® IN THE TREATMENT OF 34 MENOPAUSE SYMPTOMS
Other alternative therapies should be studied to TABLE I.—Menopause symptom Score Questionnaire at the inclusion
improve health maintenance and make menopause and after 8 weeks of treatment.
manageable. Therapy based upon phytoestrogens 4 Period
showed no evidence of effectiveness other than some Variables Inclusion After 8 weeks
sporadic effect on hot flashes and night sweats. A
strong placebo effect was also found in most of the Product Control Product Control
trials with reduction of episodes up to more than 50%. Common symptoms
One of the most used remedies is black cohosh, which Hot flashes 3.1±0.3 3.0±0.3 1.1±0.5 a 3.0±0.4
contains a preparation that has been found to improve Night sweats 3.1±0.3 3.2±0.4 2.1±0.8 2.5±0.2
vasomotor symptoms; but further studies are needed Irregular period 3.7±0.1 3.5±0.3 2.1±1.1 3.8±0.2
Loss of libido 2.1±1.1 3.0±0.4 1.1±0.6 a 3.4±0.3
due to the conflicting results of treatment with this Vaginal dryness 2.2±1.1 2.5±0.2 1.1±0.3 a 2.2±0.4
herbal preparation.5 Mood swing 1.8±0.9 2.0±0.3 1.1±0.4 2.2±0.1
Since there is a current gap in the treatment of Total score b 16±4.7 17±1.9 9±4.1 17 ±1.7
menopausal symptoms, several new therapies are under Changes
way that may help to alleviate the unmet needs. One Fatigue 2.1±1.1 2.0±0.1 1.2±0.4 2.2±0.1
new therapy that has shown some positive activity in Hair loss 1.3±1.2 1.4±0.2 1.1±0.5 2.0±0.2
Sleep disorders 2.1±0.9 2.0±0.1 1.1±0.4 a 2.4±0.2
preliminary studies (data on file) is based upon the Difficult concentrating 2.5±0.4 2.2±0.2 1.3±0.6 2.4±0.3
combination of calcium, vitamin D and three antiox- Memory lapses 2.8±0.3 3.0±0.2 2.1±1.1 3.3±0.2
idants: licopene, astaxanthin and bioflavonoids. Dizziness 2.4±0.9 2.2±0.3 2.1±0.5 2.2±0.1
Weight gain 1.7±0.9 1.5±0.2 1.2±0.9 2.0±2.2
Calcium and vitamin D3 6-9 are known to be beneficial Incontinence 3.2±0.5 3.0±0.2 1.2±0.3 a 3.2±0.2
in the reduction of cardiovascular events,6 for bone Bloating 1.1±0.8 1.2±0.2 0.9±0.4 2.0±0.2
health,7 and for quality of life.8 The antioxidants used Allergies 2.5±0.2 2.0±0.2 0.9±1.1 2.5±0.2
Brittle nails 1.2±0.5 1.2±0.2 1.0±0.4 2.2±0.2
were bioflavonoids, which acted as circulating antiox- Change in odor 3.1±0.4 3.0±0.3 2.3±0.3 3.1±0.1
idants, and two carotenoids (lycopnene and astaxan- Irregular heartbeat 1.9±0.3 2.0 ±0.2 1.1±0.4 2.2±0.1
Depression 2.9±0.2 2.2±0.3 1.1±0.3 a 2.5±0.2
tinea), which acted as membrane antioxidants. Anxiety 3.1±0.7 3.0±0.3 1.4±0.6 a 3.3±0.1
Bioflavonoids were included because some of them Irritability 2.2±1.2 2.0±0.2 1.1±0.3 2.1±0.3
have been found to be beneficial in the management of Panic disorder 3.1±0.5 3.3±0.2 0.8±0.3 a 3.1±0.2
osteoarthritis in the past 10-15 and in more recent clin- Total score b 39 ±13.2 37 ±3.9 22 ±9.4 43 ±5.8
ical trials.16, 17 In particular, citrus bioflavonoids have Pains
been approved by the European Food Safety Agency Breast pain 2.6±1.2 2.3±0.2 1.3±0.3 a 2.7±0.1
(EFSA) for the healthy maintenance of joints.18-25 Headaches 3.2±0.3 3.0±0.4 2.2±0.3 3.4±0.3
Joint pain 2.7±0.6 2.2±0.3 0.9±0.3 a 2.8±0.2
Lycopene was added to the formula because its lev- Burning tongue 1.1±0.5 1.0±0.4 1.0±0.2 1.3±0.1
els in postmenopausal osteoporosis are lower,10 and it was Electric shocks 2.5±0.2 2.2±0.1 0.6±0.2 a 2.6±0.3
Digestive problem 3.1±0.3 3.0±0.2 1.1±0.4 a 3.3±0.3
shown to decrease bone resorption.11 Furthermore, it is Gum problems 2.2±0.5 2.0±0.1 1.2±0.3 2.2±0.1
the most concentrated carotenoid in lymphocytes 12 and Muscle tension 2.8±0.3 2.3±0.1 1.1±0.3 2.2±0.1
may help in the reduction of inflammation processes. Itchy skin 2.9±0.3 2.3±0.3 1.2±0.3 2.2±0.1
Tingling extremities 2.2±0.8 2.2±0.1 1.1±0.3 2.0±0.1
Astaxanthin was included in the formula because it is
Total score b 25±5.6 23±2.6 12 ±3.1 25 ±1.7
the most active carotenoid.13 This molecule acts as a
hydroxyl substitute in orto position to the carbonyl group Data are mean values±SD. a t test for independent data: product vs. control at 8
14 in each of the two iononic groups of the extremity of weeks PAFRAGIL® IN THE TREATMENT OF 34 MENOPAUSE SYMPTOMS BELCARO
TABLE II.—General characteristics of the two groups of women under TABLE III.—Components of Afragil® tablets.
treatment with Afragil® and placebo.
Ingredients mg
Variables Product Placebo t test
Calcium carbonate/lactate 800.0
Number 33 32 Astaxantin 0.27
Age 43±3.50 42±3.2 N S Lycopene 1.0
Common symptoms* 16±4.70 17±1.9 N S Vit D3 0.23
Changes 39±13.2 37±3.9 N S Bioflavonoids from Citrus 33.0
Pains 25±5.60 23±2.6 N S
Data are mean values±SD.
symptoms were discussed after the compilation of the
questionnaire to clarify any items that were unclear
of 32 women took no treatment. Both groups were to the participants.
controlled for a period of eight weeks evaluating
signs/symptoms related to menopause. Products
The criteria of inclusion were: age >40 andBELCARO AFRAGIL® IN THE TREATMENT OF 34 MENOPAUSE SYMPTOMS study except one in the control group that did not come TABLE IV.—Variations in plasma free radicals. to the control after eight weeks. Placebo Treatment P Ns=t test for independent data P>0.05 (Table II) for dtails. PL free radicals Inclusion 388.4;28.3 384.2;22.5 NS From the data reported in Table II, it is evident that Carr Units 4 weeks 321.3;33.4 392.3;26.2 0.05 the average value of the three blocks of symptoms are 8 weeks 311;23.2,0 388.3;26,0 0.05 very similar, the only difference being the SD, which are much lower in the control group due to a minimal fluctuation of the items compared to the treated group. four and eight weeks. At eight weeks the decrease was Treatment was well tolerated since complaints sustained. In controls there was a significantly lower regarding taste were reported in just a few cases, and variation (not significant). These results indicate the the compliance was >97%. important protective effects of the product on oxidative The complete set of signs/symptoms is reported in stress. Table II. Because of the differences in the SD at the baseline, the total scores of the three blocks of symp- toms were not considered in the evaluation of the activ- Discussion ity, and the difference between the two groups was based upon each sign/symptom only. The results of this pilot study indicate that it is pos- The controls did not show any evident “placebo” effect, sible to improve signs and symptoms related to the since very few items were favorably modified (night climacteric state by using natural products. The use sweats in particular, and minimally vaginal dryness, mus- of a preparation containing black-cohosh (Cimifuga cle tension and itchy skin), during the study. On the con- racemosa) was recently shown to be effective in the trary, most of the items had the tendency to worsen. treatment of some of the common symptoms of the The total average score (all three blocks of vari- climacteric period,5 including hot flashes, profuse ables) was reduced by about 48% in the treatment sweating and sleep disturbances. However, conflicting group, whereas in the control group there was an results are reported in the literature,19 and there is also increase of about 10%. concern about its safety with long-term administra- A significant modification of the variables in almost tion, because a “natural product” does not necessari- all the signs/symptoms was shown with the treatment ly mean a “safe product”. For instance, this plant con- with MF Afragil® compared to controls. However, tains mainly triterpens glicosydes (e.g., cycloartanes), only those exceeding the cut-off of P>0.01 were con- and also some unknown compound with serotoniner- sidered as a “positive effect”. Modification of night gic activity, which could be responsible for the CNS sweats, hair loss, dizziness, brittle nails and burning action. However, the activity can be different accord- tongue were similar for both groups. ing to the part of the plant that is used, and if prepara- Despite the fact that the sample size was determined tion is not properly standardized.17 by the hot flashes score, most of the variables have a All the ingredients present in MF Afragil ® are sufficient statistical power (
AFRAGIL® IN THE TREATMENT OF 34 MENOPAUSE SYMPTOMS BELCARO
Aromatase expression and circulating C19 precur- Finally, the MSSQ was found to be helpful in deter-
sor of estrogens are essential for estrogen synthesis mining the climacteric condition because it is so sim-
in various tissue to partially substitute the synthesis ple to fill out. To our knowledge, this is the first time
of the ovarian granulose cells no longer efficient in that this questionnaire has been used in a parallel study
the climacteric status. comparing treatment with no treatment. All partici-
In many tissues (e.g., breast, bone, vasculature, pants filled out all the variables, and very few questions
lipids) a fundamental step of synthesis is represented were posed about the meaning of the items.
by the cytochrome CYP19, which needs NADPH, and An important element can be drawn from these
the flavoproteine NADPH-cytochrome P450 as cofac- results, which are related to low dosages of antioxidants
tors.23 This means that ATP and reducing equivalents contained in MF Afragil®. The term MF means “mod-
are needed; in other words, antioxidants may improve ulator” and indicates also that the combination of many
the residual synthesis of estrogens. ad hoc natural products such as flavonoids, lycopene,
A similar effect can be determined by the protection and astaxantin, at low dosages, can result in a syner-
of the cellular membrane from oxidative stress in the gistic activity. With these ingredients administered at
case of hot flashes. The pathogenesis of hot flashes is these dosages, side effects are not expected and, if
still under discussion and poorly defined. However, they do occur, they will not be severe or harmful.
it seems that hot flashes are determined by dysfunction Separate elements such as calcium plus vitamin D3,
of the central thermoregulatory center (CTC) due to the or antioxidants only were not found as efficient (data
reduction in estrogen levels, which induces a nega- on file under publication) in reducing the climacteric
tive feedback of the pituitary gonadotropins.24 burden.
Hypothe-tically, this dysregulation of the CTC can be The added benefits of this product on PFR that were
due to a reduction of cerebral blood glucose 25 that observed are also important since we do not know
induces a compensative vasodilation to increase the how many signs/symptoms associated to menopause
glucose available for the uptake of the GLUT 1 recep- are related to increased oxidative stress or may be
tors. This vasodilation is considered capable of increas- dependent on increased PFR.26
ing the temperature of the CTC of the minimal amount
that can trigger the peripheral reaction as hot flashes.
These GLUT 1 receptors are membrane receptors that Conclusions
can become less efficient in case of oxidation of their
In conclusion, in a parallel short term registry study
membrane phospholipids, or even by the oxidation of
the combination of calcium, vitamin D3 and ad hoc
cell membrane phospholipids where they are located.
antioxidants was found to reduce significantly the
Lycopene and astaxantin are known to be powerful
symptoms of the climacteric status and to improve the
membrane antioxidants that can preserve from phos- quality of life. More extensive studies and a longer
pholipids oxidation (both on cellular membranes or period of treatment are needed to determine the con-
GLUT receptors), with the final result to make the tinuity of the activity and the improvement of ostero-
GLUT 1 more efficient. porosis.
Citrus bioflavonoids have been recently approved by
the EFSA (31 July 2009 EFSA; Claim ID 1799) as
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