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Steels, Elizabeth, Steele, Megan, Harold, Marianne, Adams, L., & Coul-son, Samantha(2018)A double-blind, randomized, placebo-controlled trial evaluating safety andefficacy of an Ayurvedic botanical formulation in reducing menopausalsymptoms in otherwise healthy women.Journal of Herbal Medicine, 11, pp. 30-35.
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https://doi.org/10.1016/j.hermed.2018.01.001
Accepted Manuscript
Title: A Double-Blind, Randomized, Placebo-Controlled TrialEvaluating Safety and Efficacy of an Ayurvedic BotanicalFormulation in Reducing Menopausal Symptoms inOtherwise Healthy Women
Authors: E. Steels, M. Steele, M. Harold, L. Adams, S.Coulson
PII: S2210-8033(18)30001-0DOI: https://doi.org/10.1016/j.hermed.2018.01.001Reference: HERMED 205
To appear in:
Received date: 22-11-2016Revised date: 7-6-2017Accepted date: 7-1-2018
Please cite this article as: Steels, E., Steele, M., Harold, M., Adams, L.,Coulson, S., A Double-Blind, Randomized, Placebo-Controlled Trial EvaluatingSafety and Efficacy of an Ayurvedic Botanical Formulation in ReducingMenopausal Symptoms in Otherwise Healthy Women.Journal of Herbal Medicinehttps://doi.org/10.1016/j.hermed.2018.01.001
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1
A Double-Blind, Randomized, Placebo-Controlled Trial Evaluating
Safety and Efficacy of an Ayurvedic Botanical Formulation in
Reducing Menopausal Symptoms in Otherwise Healthy Women.
Efficacy of Ayurvedic Formulation in Reducing Menopausal Symptoms
Steels E, a,b, Steele M, c,d, Harold M,a Adams L,a Coulson S,b,e
a. Integrated Health Group Pty. Ltd, Brisbane, QLD Australia b. The University of Sydney, Sydney Medical School, NSW, Australia c. Queensland University of Technology, Brisbane QLD, Australia d. Research Institute Havelhöhe, Hospital Havelhöhe, Berlin, Germany e. The BRIDI Centre Pty Ltd, Brisbane, QLD, Australia
Corresponding author:
Dr Elizabeth Steels
Telephone: 0431 003 929
Funding source: This work was supported by Gencor Pacific, Discovery Bay, Hong Kong.
Abstract
Aims The aim of the present study was to examine the safety and efficacy of a formulated
Ayurvedic botanical combination in reducing vasomotor and other menopause-associated
symptoms in otherwise healthy women.
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Methods This was a double-blind, randomized, placebo-controlled trial conducted with 117
healthy women, aged 40 to 65 years using a formulated Ayurvedic medicine composed of
75mg Tinospora Cardifolia, 100mg Asparagus racemosus, 100mg Withania somnifera and
225mg Commiphora mukul per capsule, administered as one capsule twice per day over a
period of 12 weeks. The primary outcome measure was menopausal symptoms assessed by
the validated Menopause-Specific Quality of Life (MENQOL) questionnaire. The secondary
outcome measures included a patient-reported diary of vasomotor symptoms, serum hormone
levels and health indices (body weight, blood pressure, haematological and biochemistry
markers).
Results A significant difference was demonstrated for the total MENQOL score and the
vasomotor (p < 0.001), psychosocial (p < 0.001), physical (p = 0.02) and sexual domains (p <
0.001) between the active treatment and placebo groups after 12 weeks. There was a
significant reduction in total hot flushes, daytime hot flushes and night sweats in the active
treatment group compared to the placebo group (p ≤ 0.001). There were no significant
changes observed in serum hormone levels or health indices between the active and the
placebo group.
Conclusion This study demonstrated a combination of Tinospora cardifolia, Asparagus
racemosus, Withania somnifera and Commiphora mukul to be a safe and effective treatment
for reducing menopausal symptoms in healthy menopausal women over a duration of 12
weeks.
Keywords
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Tinospora cardifolia, Asparagus racemosus, Withania somnifera, Commiphora mukul,
menopause, hot flushes
1. INTRODUCTION
The transition into menopause is typically a gradual process occurring over a number of years
with a loss of follicular function becoming noticeable usually around the age of 40. Early
hormonal changes include substantial fluctuations in circulating follicle stimulating hormone
(FSH), Inhibin B and oestradiol levels (Woods et al., 2014). The perimenopausal phase is
defined as having vasomotor symptoms (hot flushes and night sweats) and irregular periods;
menopause is defined as physiological termination of menstruation due to decreased ovarian
function (Lumsden, 2016; Hendrix, 2011). Standard management of menopause is based on
alleviating the most commonly reported and troublesome symptoms; to reduce vasomotor
symptoms and improve sexual function by prescribing hormone replacement therapy or the
use of specific botanical medicines.
A limited number of clinical studies have demonstrated that soy isoflavones and
Trifolium pratense (red clover) isoflavones provide significant improvement in hot flushes,
vaginal dryness, sleep, mood and libido (Lipovac et al., 2011; Franco et al., 2016). Actaea
racemose (Black cohosh) may reduce vasomotor, psychiatric and sexual symptoms (Leach &
Moore, 2012; Mohammad-Alizadeh-Charandabi et al., 2013) while Trigonella foenum-
graecum extract (Steels et al., 2017) and Pinus pinaster (maritime pine bark) (Yang et al.,
2017) reduce vasomotor symptoms and increase libido in menopausal women. It has
however, recently been acknowledged that the menopause consists of a spectrum of other
symptoms and identification of the specific cluster of symptoms may be useful in determining
the most appropriate treatment for individual women (Woods 2015; Woods et al., 2016).
Furthermore, it is now recognized that transition into and through the menopause is associated
with elevated states of anxiety and depression and these, therefore, must also be addressed
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(Siegel & Mathews, 2015). The selected botanicals, Tinospora cardifolia, Asparagus
racemosus, Withania somnifera, and Commiphora mukul, in the investigational product, were
derived from the traditional Ayurvedic medical paradigm to balance the female reproductive
system and modulate inflammatory responses, liver function and the stress response, in order
to address the symptoms of menopause via a multi-systems approach.
Tinospora cordifolia has a variety of active phytochemical constituents including
aliphatic compounds, alkaloids, steroids, lactones, glycosides, sesquiterpenoids,
polysaccharides, various fatty acids and essential oils (Hussain et al., 2015; Saha & Ghoash,
2012; Upadhyay et al., 2010). The plant also contains arabinogalactan, a branched
polysaccharide with prebiotic and immunological activity (Mishra et al., 2013). Asparagus
racemosus contains phytochemical constituents such as steroidal saponins, alkaloids, quercetin
and glycosides of quercetin. In Ayurvedic medicine, it has been used to treat conditions relating
to the female reproductive system including menopause, the immune system and the nervous
system (Potduang et al., 2008). Withania somnifera also referred to as Indian ginseng and
Ashwagandha (Dar et al., 2015) is an important herb within the Ayurvedic and Unani systems
of medicine. Phytochemical constituents of the Withania somnifera plant include alkaloids
(withanine), steroidal lactones, steroids (β-sitosterol, diosgenin, sitoinosides), flavonoids
(quercetin) and nitrogen-containing compounds (withanol) (Dar, 2015). Scientific research
(animal and in vitro) has demonstrated numerous biological activities inherent to Withania
somnifera with anti-stress and neuroprotective functions (Yenesetti, et al., 2016; Dar, 2015) It
has also been reported to modulate the γ-amino butyric acid (GABA) and acetylcholine
neurotransmitters (Mehta et al., 1991; Kulkarni & George, 1996). Commiphora mukul contains
phytochemical constituents that are responsible for its therapeutic action including volatile oils
(myrcene, di- and polymyrcene, d-limonene, coneole), steroids (guggulsterones and
guggulsterols), flavonoids (muscanone, naringenin, quercetin), guggultetrols, lignans (sesamin
and diayangambin), as well as sugars and amino acids (Sarup et al., 2015). Commiphora mukul
is traditionally used in Ayurvedic medicine for obesity, diabetes and inflammatory conditions such
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as arthritis (Sarup et al., 2015; Shen et al., 2012).
The aim of the present study is to investigate the efficacy of a formulated Ayurvedic
botanical medicine comprising a combination of Tinospora cardifolia, Asparagus racemosus,
Withania somnifera and Commiphora mukul in supporting women through menopause,
reducing associated symptomology and/or modulating the stress response.
2. MATERIALS AND METHODS
2.1. Study Design
This was a single-site, double-blind, randomized, placebo-controlled clinical trial of 12 weeks
duration to assess the safety and efficacy of a formulated Ayurvedic medicine in reducing
symptoms of menopause in otherwise healthy women. It was conducted between November
2014 and March 2016 in Brisbane, Australia. The study was conducted in accordance with the
Principles of the Declaration of Helsinki and was approved by the Queensland University
Clinical Trial Human Research Ethics Committee. The trial was registered with the Australian
New Zealand Clinical Trials Registry (Trial ID: ACTRN12615000324516) and a clinical trial
notification was submitted to the Therapeutic Goods Agency.
2.2. Study Population
Participants were recruited through the contract research organization (CRO) subject
database and via public media avenues. The inclusion criteria required participants to be aged
between 40 and 65 years; to be experiencing menopausal symptoms including the presence
of hot flushes and/or night sweats scoring greater than ‘mild’ on the Menopause-Specific
Quality of Life Questionnaire (MENQOL). Women were required to be in good general health
and able to adhere to protocol requirements. Potential participants were excluded if they had
been using hormone replacement or herbal medicines for menopausal symptoms in the month
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prior to trial commencement or were currently on other investigational product(s). Women
were also excluded if they had a previous history, presence, or suspicion of oestrogen-
dependent neoplasia, neoplastic disease or treatment for any neoplastic disease within the
previous 2 years; had a partial or total hysterectomy; had active or a recent history (in the last
6 months) of thromboembolic disease; had a history of cerebrovascular accident, stroke, or
transient ischemia or had major depressive disorder, bipolar disorder, psychotic disorder or
generalized anxiety disorder requiring therapy. Women with uncontrolled diabetes, high
cholesterol or hypertension, alcohol or drug dependency were also excluded.
2.3. Intervention
The investigational product was a formulated Ayurvedic medicine (Genopause®) containing
75mg Tinospora cardifolia (spray-dried ethanolic extract of the dried stem), 100mg Asparagus
racemosus (spray-dried aqueous extract of the dried root), 100mg Withania somnifera (spray-
dried aqueous extract of the dried root) and 225mg Commiphora mukul (spray-dried ethanolic
extract of the gum exudate) in a 2-piece hard, opaque gelatin capsule. The placebo product
contained maltodextrin only, also in a 2-piece hard, opaque gelatin capsule, indistinguishable
from the investigational product. The daily dosage of the investigational products was one
capsule, twice daily (taken with breakfast and the evening meal). The investigational and
placebo product were supplied by Gencor Pacific, Hong Kong and manufactured by AZPA
Pharmaceuticals, Australia. Plant materials were identified by Dr.K.S.Krishnan of the National
Institute of Science Communication and Informatics Research, New Delhi, India. Identification
reference codes were assigned to each plant specimen - Commiphora mukul
(NISCAIR/RHMD/Consult/2016/2982-09-21); Tinospora cardifolia
(NISCAIR/RHMD/Consult/2016/2996-23-10); Asparagus racemosus
(NISCAIR/RHMD/Consult/08 – 09/1087/118/03) and Withania somnifera
(NISCAIR/RHMD/Consult/2014/2378/158-1).
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2.4. Randomization, Blinding and Monitoring
Randomization was performed independently of the investigators using Random Allocation
Software (version 1.0, May 2004). The investigational and placebo product were packed into
high-density polyethylene opaque bottles that were identical in appearance and blinded
(numbered) before being provided to the investigators. After preliminary telephone screening,
eligible participants attended a baseline interview to enrol in the study. They provided written
informed consent; completed medical history and lifestyle questionnaires (including the
MENQOL) and body weight and blood pressure were measured. Participants were provided
with Queensland Medical Laboratory (QML) pathology request forms for blood collection and
a Symptom Diary and were randomly allocated to the active treatment or placebo group.
Participants were monitored for compliance by telephone and email communications and the
number of returned capsules were counted at completion of study to determine dosage
adherence.
2.5. Objective and Outcomes
2.5.1. Primary outcome
The primary outcome measure was the validated Menopause-Specific Quality of Life
Questionnaire. The MENQOL assesses the participants’ subjective symptoms that can
significantly impact on a woman’s quality of life. It is self-administered and consists of a total
of 29 items in a Likert-scale format. Each item assesses the impact of one of four domains of
menopausal symptoms, as experienced over the previous 4 weeks, including vasomotor,
psychosocial, physical and sexual symptoms (Hilditch et al., 1996).
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2.5.2. Secondary outcomes
The vasomotor symptoms were assessed independently from the MENQOL, with the number
of daytime hot flushes and night sweats experienced by participants recorded over a 7-day
period at baseline and at each time point of week 4, week 8 and week 12. The serum hormone
profiles included oestradiol, progesterone, testosterone, free testosterone,
dehydroepiandrosterone (DHEA), luteinizing hormone (LH), follicle stimulating hormone (LSH)
and sex hormone binding globulin (SHBG) and were measured at baseline and again at week
12. These were taken in a fasting state, at the same time of day (between 8am and 9am) to
minimize daily variations in hormonal levels. Safety measurements included body weight,
blood pressure, haematological parameters and biochemistry including fasting blood glucose
(FBG), full blood count (FBC), electrolyte / liver function (E/LFT), total cholesterol (TC),
triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein
cholesterol (HDL-C), performed at baseline and week 12. Blood samples were collected and
analysed by QML pathology using standard validated protocols. Any adverse events were
documented by participants in their study diaries over the 12 weeks of the study. Participants
were instructed to alert the study coordinators if any adverse events were experienced.
2.6. Sample Size and Statistical Analysis
A minimum number of 49 participants per group were required to achieve a statistical power
of 80% on the basis of a 20% improvement in symptoms as measured by the total domain
score of the MENQOL. Demographic data were summarized by mean and standard deviation
(SD) or as proportions. The MENQOL total and domain scores were analyzed using a
generalized estimating equations (GEE) model with an autoregressive covariance structure to
account for the multiple observations per person. The number of total flushes, day-time hot
flushes and night sweats during four seven-day periods were described as mean ± SD and
analyzed using GEE with an autoregressive covariance structure and Poisson distribution.
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The hormone data were nonparametric and described as median and interquartile range
(IQR). For both treatment groups, baseline hormone levels were compared to levels at week
12 using the Wilcoxon test. All analyses were conducted in R version 3.3.1 and GEE models
were run using the geeglm function in the geepack package.
3. RESULTS
3.1. Demographics and baseline data
A total of 180 women were assessed for eligibility from which a total of 117 women were
eligible and were recruited into the study, with 61 women randomized to the active treatment
group and 56 randomized to the placebo group. From the active treatment group, 7 women
withdrew allowing for 54 evaluable participants and from the placebo group 6 women withdrew
allowing for 50 evaluable participants (Figure 1). The active treatment and placebo groups
were well matched at baseline. The mean age of women in the active treatment group was
53.2 ± 3.8 years while in the placebo group was 53.6 ± 4.0 years. The mean body weight was
comparable at baseline between the active and placebo groups, 71.5 ± 11.4 kg and 71.5 ±
13.7 kg, respectively. In the active treatment group, 46 (85.2%) women reported being married
or in a relationship, compared to 33 (66%) women in the placebo group (Table 1).
(Figure 1. Flow diagram of participant recruitment, follow-up and analysis)
Table 1. Demographic baseline data
Characteristics Active group
(n = 54)
Placebo group
(n = 50)
p-value
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Age (years), mean (SD) 53.2 (3.8) 53.6 (4.0) 0.69
BMI (kg/m2), mean (SD) 26.7 (4.4) 26.7 (4.6)
(N=37)
0.64
Weight (kg), mean (SD) 71.5 (11.4) 71.5 (13.7) 0.67
Waist : hip ratio, mean (SD) 0.8 (0.1) 0.8 (0.1) 0.37
Current smokers, n (%) 6 (11) 5 (10) 0.15
Social drinkers, n (%) 36 (67) 29 (58) 0.95
Undertake regular weekly exercise, n (%) 42 (78) 33 (66) 0.79
Married or in a relationship 46 (85.2) 33 (66) 0.02
3.2. Outcome measures
3.2.1. Primary outcome
The severity of menopausal symptoms was assessed using the validated MENQOL
questionnaire at baseline, 4-weeks, 8-weeks and 12-weeks. There was no significant
difference in total MENQOL score at baseline between the two groups (p = 0.5). There was a
significant reduction in the total MENQOL score over 12 weeks in the active treatment group
compared to placebo, 26.4% versus 2.3%, respectively (p < 0.001). There were significant
reductions in all of the four domains: vasomotor, psychosocial, physical and sexual domains
(Table 2). The vasomotor domain symptoms including “day flushes”, “night sweats” and
“sweating” were significantly improved in the active treatment group compared to the placebo
group at week-12 (p<0.001). There was a statistically significant improvement in the
psychosocial domain questions of “accomplishing less tasks” (p = 0.013), “feeling depressed
or blue” (p = 0.022) and “being impatient with other people” (p = 0.018) in the active treatment
group compared to the placebo group at week-12. Within the physical domain, there was a
statistically significant improvement in the questions “feeling worn out” (p = 0.003), “aches in
the back of the neck or head” (p = 0.048) and “decreased stamina” (p = 0.044) and “decreased
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facial hair” (p = 0.010). In the sexual domain, there was a statistically significant improvement
in questions relating to “vaginal dryness” (p = 0.031) and “avoidance of intimacy” (p = 0.005)
within the active treatment group compared to placebo (Table 2).
Table 2. Mean MENQOL scores (total and for each individual domain) between the
active and placebo groups at baseline, week-4, week-8 and week-12.
Time T0 weeks
Mean ± SD
T4 weeks
Mean ± SD
T8 weeks
Mean ± SD
T12 weeks
Mean ± SD
P value*
Vasomotor
Active 5.4±1.5 4.0±1.4 3.5±1.5 3.8±1.7 <0.001
Placebo 4.8±1.8 5.1±1.7 5.0±1.8 5.0±1.8
Psychosocial
Active 4.1±1.6 3.2±1.5 3.0±1.4 3.2±1.5
<0.001
Placebo 4.2±1.9 4.3±2.1 4.1±1.9 4.1±1.9
Physical
Active 4.5±1.3 3.7±1.2 3.3±1.1 3.6±1.3
0.002
Placebo 4.2±1.6 4.0±1.5 3.8±1.5 3.9±1.5
Sexual
Active 4.2±2.2 3.5±1.9 3.2±1.9 2.9±1.9
<0.001
Placebo 4.3±2.4 4.4±2.4 4.0±2.4 4.1±2.4
TOTAL
Active 18.2±3.9 14.4±3.8 13.0±3.8 13.4±4.2
<0.001
Placebo 17.5±5.6 17.8±5.8 16.9±5.8 17.1±5.5
* Generalized estimating equations *Significance at p<0.05, GEE, autoregressive covariance used.
3.2.2. Secondary outcomes
The median number of combined daytime hot flushes and night sweats (total) in the active
treatment and placebo groups was similar at baseline (W=1000, p=0.4). Participants in both
active and placebo groups reported more daytime hot flushes than night sweats (Table 3). A
significant reduction in total flushes was observed in the active treatment group (p<0.001),
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reducing by 43% at 4-weeks from baseline, by 52% at 8-weeks and by 67% at 12 weeks. In
the placebo group, hot flushes did reduce by 19% by week 8 with no further improvement
observed. There was a significant reduction in the active treatment group in both the daytime
flushes (p<0.001) and night sweats (p<0.001) compared to placebo over the 12-week
treatment. These results are consistent with the results observed for the vasomotor domain
symptoms of the MENQOL.
Table 3. Average total flushes, daytime hot flushes and night sweats for the formulated
Ayurvedic medicine and placebo at baseline, week-4, week-8 and week-12.
Baseline
Median (IQR)
Week 4
Median (IQR)
% change
Week 8
Median (IQR)
% change
Week 12
Median (range)
% change
p-value
Day-
time
Hot
Flushes
Active 28 (14-42)
20 (5-29)
↓ 30%
14 (2-25)
↓ 50%
10 (3-24)
↓ 64%
<0.001
Placebo 18 (7-38)
17 (7-36)
↓ 6%
18 (8-38)
0%
22 (10-38)
↑ 22%
Night
Sweats
Active 14 (7-24)
7 (1-16)
↓ 50%
7 (1-13)
↓ 50%
4 (0-12)
↓ 71%
<0.001
Placebo 11 (3-28)
7 (1-19)
↓ 36%
8 (0-16)
↓ 27%
10 (1-21)
↓ 9%
Total
Flushes
Active 42 (23-60)
24 (9-44)
↓ 43%
20 (4-41)
↓ 52%
14 (5-35)
↓ 67%
<0.001
Placebo 36 (14-56)
29 (14-54)
↓ 19%
29 (14-53)
↓ 19%
37 (15-59)
↑ 3%
The results are taken from a 7-day diary completed at Baseline, week-4, week-8 and week-12.
*Significance at p<0.05, GEE, auto-regression covariance, Poisson distribution used.
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3.2.3 Serum hormone levels
Serum oestradiol levels were comparable between the two groups at baseline (W=1147,
p=0.9). The median serum oestradiol levels in the active treatment group and placebo group
were 50 pmol/L (IQR = <42-148) and 60 pmol/L (IQR = <42-148), respectively (Table 4). The
lower limit of detection for oestradiol was 42pmol/L, of which 43% of women in the active group
and 42% in the placebo group were already below at baseline. These levels were indicative
of levels expected for postmenopausal women. In both groups, oestradiol levels were
negatively correlated with age at baseline (active: r2 = -0.44, p = 0.001, placebo: r2 = -0.43, p
= 0.002). There was no correlation between BMI and oestradiol levels. In the active group,
oestradiol increased from 50 pmol/L at baseline to 60 pmol/L at 12 weeks, however this
difference was not statistically significant. There were no statistically significant differences (all
p>0.5) between hormone levels at baseline and week 12 in the active or placebo group (Table
4).
Table 4. Serum hormone levels for the formulated Ayurvedic medicine and placebo at
baseline and week-12.
Hormones
Active group (n=54) Median (IQR)
Placebo Group (n=50) Median (IQR)
Baseline Week 12 Baseline Week 12
Estradiol (pmol/L) 50 (<42*-148) 60 (<42*-120) 60 (<42*-270) 60 (<42*-180)
Progesterone (mmol/L) <1* <1* <1* <1*
Testosterone (mmol/L) 1 (0.7-1.3) 0.9 (0.7-1.3) 1 (0.5-1.3) 1 (0.7-1.4)
Free Testosterone (pmol/L)
11 (7-17) 13 (9-17) 12 (8-19) 12 (8-18)
LH (IU/L) 60 (42-75) 60 (33-80) 55 (37-70) 55 (38-70)
FSH (IU/L) 130 (82-215) 143 (70-220) 145 (110-185) 140 (101-188)
SHBG (mmol/L) 60 (45-80) 58 (42-69) 62 (38-78) 56 (42-76)
*Lower limit of detection
Significance at p <0.05, t-tests were used. No significant changes were detected.
3.3. Health Indices and adverse events
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No changes were observed in blood pressure, body weight, blood glucose levels, lipid profiles
(total cholesterol, triglycerides, LDL-C or HDL-C), total protein or albumin after 12 weeks of
treatment within the active or placebo group (Table 5). Furthermore, electrolytes, liver
enzymes and renal function tests remained within reference range in both active and placebo
groups. The investigational product was well tolerated over the 12-week study duration with
no major adverse events reported.
Table 5: Effect of formulated Ayurvedic medicine and placebo on health indices at
baseline and week-12.
Health Indices Active group (n=54) Mean (SD)
Placebo Group (n=50) Mean (SD)
Baseline Week 12 Baseline Week 12
Blood pressure (mmHg)
Systolic
Diastolic
120.3 (10.8)
78.3 (8.6)
119.7 (9.5)
77.2 (6.9)
121.6 (13.1)
78.1 (7.7)
120.2 (10.2)
77.8 (6.9)
Weight (kg) 71.5 (11.4) 71.8 (11.9) 71.5 (13.7) 71.5 (13.7)
Fasting blood glucose
(3.0-6.0 mmol/L)*
4.9 (0.4) 5.0 (0.5) 4.9 (0.7) 4.9 (0.6)
Total Cholesterol
(3.6-6.9 mmol/L)*
5.6 (0.8) 5.5 (0.9) 5.5 (0.9) 5.4 (0.8)
LDL-C
(0.3-2.2 mmol/L)*
3.1 (0.8) 3.1 (0.8) 3.0 (0.9) 2.9 (0.8)
HDL-C
(0.3-2.2 mmol/L)*
1.8 (0.5) 1.8 (0.5) 1.8 (0.5) 1.9 (0.5)
HDL-C : LDL-C ratio 3.2 (0.9) 3.3 (1.1) 3.2 (1.0) 3.1 (0.9)
Triglycerides
(0.3-2.2 mmol/L)*
1.0 (0.6) 1.0 (0.8) 1.1 (0.7) 1.0 (0.7)
Red cell count
(3.6-5.2 x1012/L)* 4.6 (0.3) 4.6 (0.3) 3.6 (0.3) 4.6 (3)
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Haematocrit
(0.33-0.46)* 0.41 (0.03) 0.41 (0.02) 0.41 (0.03) 0.47 (0.05)
Mean cell volume
(80-98 fL)* 90 (3.9) 90 (5) 89 (5) 90 (8)
Mean cell haemoglobin
(27-35 pg)* 30.0 (1) 30 (2) 29 (2) 30 (2)
Total protein
(60-80 g/L)* 71 (4) 70 (5) 69 (4) 70 (4)
Albumin
(35-55 g/L)* 42 (3) 41 (2) 41 (3) 41 (3)
* QML reference ranges
Health indices were assessed at baseline and week-12. Significance at p <0.05, t-tests were used. No
significant changes were detected.
4. Discussion
This clinical study examined the therapeutic efficacy of a formulated Ayurvedic medicine
containing Tinospora cardifolia, Asparagus racemosus, Withania somnifera and Commiphora
mukul in relieving menopausal symptoms in otherwise healthy women. These botanicals have
not, to the best of the authors’ knowledge, previously been investigated individually or in this
specific combination for the treatment of menopausal symptoms. The selected botanicals
were derived from the traditional Ayurvedic medical paradigm to balance the female
reproductive system, inflammatory responses and liver parameters and to modulate the stress
response; however little scientific validation for such effects exists. The results of this study
demonstrated that supplementation with this formulation resulted in a significant improvement
in vasomotor symptoms, with a significant reduction in reported daily total hot flushes, daytime
flushes and night sweats. There was also a significant improvement in sexual function that
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was accompanied by improvements in physical and psychosocial symptoms. The
improvement in menopausal symptoms was not associated with changes in the levels of
DHEA, estradiol or testosterone. Furthermore, there were no statistically significant changes
in red blood cells, blood glucose, lipid metabolism, liver and renal markers after 12 weeks of
supplementation.
It is well accepted that psychosocial symptoms of anxiety, irritability, nervousness,
stress and depression are common during the menopausal transition phase. This supports
previous research demonstrating an association between high anxiety and sexual dysfunction
in early post-menopausal women (Santoro & Taylor, 2011; Santoro, 2016). It is likely that the
addition of Withania somnifera and Asparagus racemosus contributed to the efficacy in reducing
psychosocial symptoms. In a recent systematic review, Pratte et al. (2014) concluded that
supplementation of Withania somnifera was more effective than placebo in reducing anxiety
and stress. Furthermore, a recent study demonstrated that Withania somnifera has GABAergic
activity which may explain why key constituents of Withania somnifera exert therapeutic
activity for general anxiety disorders and provide neurological support during menopause
(Candelario et al., 2015). Most recently, Takanari et al. (2016) assessed the efficacy of an
enzyme-treated Asparagus racemosus extract on decreasing psychological stress parameters
in healthy individuals and reported it had beneficial effects against the stress response;
reducing dysphoria and fatigue, improving sleep quality and increasing salivary IgA levels.
It is possible that the improvement in sexual function could also be attributed to
Asparagus racemosus. A polyherbal formula containing Asparagus racemosus has previously
been found to be effective in reducing vasomotor symptoms of menopause (Singh & Kulkarni,
2002). The galactogogue activity of Asparagus racemosus was demonstrated in a clinical study
in which it was shown to improve prolactin levels in lactating women (Gupta & Shaw, 2011).
Moreover, a recent animal model demonstrated that a dose-dependent aqueous extract of
Asparagus racemosus significantly stimulated the secretion of hypothalamic-pituitary-gonadal
axis hormones including gonadotropin releasing hormone (GnRH), FSH, LH, estrogen and
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progesterone hormones (Jashni et al., 2016). Tinospora cardifolia and Commiphora mukul are
botanicals that have been shown to modulate liver function and have anti-inflammatory activity in
animal models. There were no changes in liver function in this study, however women were
within healthy reference ranges at baseline. A recent study reported that postmenopausal
women who had a higher BMI, demonstrated higher levels of hs-CRP which was interpreted
as low-grade chronic inflammation and hence increased cardiovascular disease risk (Alves et
al., 2016). The BMI of women in the active group ranged from 18.4 – 38.1 with 61% of this
group having a BMI higher than 25. A reduction in inflammation would therefore prove
beneficial, however inflammatory markers were not assessed in this study and therefore it
cannot be determined if this formulation reduced inflammation in this cohort. Hussain et al.
(2015) recently demonstrated Tinospora cordifolia extract to have significant anti-pyretic,
analgesic and anti-inflammatory activity in a dose-dependent manner in an animal model. The
authors suggested that the inhibition of pain, inflammation and fever was probably due to the
presence of flavonoids and alkaloids. Furthermore, Kumari et al. (2016) demonstrated that
Tinospora cordifolia modulates lipid metabolism by inhibiting cholesterol and glucoronide
synthesis. The pharmacological activity of Commiphora mukul has been demonstrated in animal
and human studies for its anti-inflammatory (Singh et al., 2003), hypolipidemic (Ulbricht et al.,
2005) and anti-diabetic activities (Bellamkonda et al., 2011), as well as the amelioration of
hypothyroidism (Panda & Kar, 2005).
The limitations to the present study included a small sample size of women
representing various stages of menopausal transition; varying levels of symptom severity and
a wide range in oestradiol levels (ranging from <42 to 1090 pmol/L). The average symptom
duration of the menopause transition period and into the postmenopausal period is
approximately 10 years; symptoms rising sharply 2 years before the final menstrual period,
peaking at 1 year after the final menstrual period and not returning to premenopausal levels
until about 8 years after the final menstrual period (Politi et al., 2008). Hence, observing
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significant hormonal changes within such a short period, when they are naturally fluctuating
and declining, is expectedly unlikely.
5. Conclusion
In conclusion, we have demonstrated that over a 12-week period, a formulated Ayurvedic
medicine containing Tinospora cardifolia, Asparagus racemosus, Withania somnifera and
Commiphora mukul is safe and effective in relieving vasomotor symptoms of menopause and
improving psychosocial and adverse sexual symptoms that are typically associated with
menopause. Further clinical and pharmacological studies, including those of longer duration,
are required to understand the mechanistic actions of this Ayurvedic botanical combination in
menopausal women.
Conflict of interest
All authors have declared no conflict of interest.
Funding
This work was supported by Gencor Pacific, Hong Kong.
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