and Estrogen/progestin replacement study (HERS)2,3
have indicated that the risks of hormone replacement
therapy (HRT) for post-menopausal women may
Women’s Health Initiative study in 20021 and Heart
Evaluation of effect of isoflavone on thyroid economy &
autoimmunity in oophorectomised women: a randomised,
double-blind, placebo-controlled trial
Niti Mittal, Debasish Hota, Pinaki Dutta*, Anil Bhansali*, Vanita Suri**, Neelam Aggarwal**,
R.K. Marwah+ & Amitava Chakrabarti
Departments of Pharmacology, *Endocrinology & **Obstetrics & Gynaecology, Postgraduate
Institute of Medical Education & Research, Chandigarh, & +Department of Endocrinology,
Institute of Nuclear Medicine & Allied Sciences, New Delhi, India
Received October 23, 2009
Background and objectives: The potential of soy isoflavones to interfere with thyroid function has been
reported. However, there are limited data regarding their effect on thyroid function and autoimmunity
in surgical menopausal women. The present study aimed to evaluate the effect of isoflavones on thyroid
function and autoimmunity, menopausal symptoms, serum follicle stimulating hormone (FSH) and
estradiol levels in oophorectomised women.
Methods: A randomized, double blind, placebo-controlled trial was conducted in 43 oophorectomised
women to evaluate the effect of soy isoflavones (75 mg/day for 12 wk) on serum thyroid profile (free T3,
free T4, TSH, TBG and anti–TPO antibody titres) assessed at baseline, 6 and 12 wk after randomization.
Assessment was also done for menopause symptom score (MSS) three weekly, and FSH and estradiol
levels at baseline and at study completion.
Results: There was a significant alteration in free T3 levels in the group receiving isoflavones (4.05 ± 0.36,
4.12 ± 0.69 and 3.76 ± 0.55 pmol/l at baseline, 6 and 12 wk, respectively; P=0.02). However, the mean
change in various thyroid parameters at 12 wk from baseline was not significantly different between
the two groups. MSS was also significantly decreased at 9 and 12 wk from baseline with isoflavones
(12.47 ± 8.15, 9.35 ± 5.23 and 9 ± 5.14 at baseline, 9 and 12 wk respectively; P=0.004) with significant
improvement in urogenital symptoms compared to placebo. Isoflavones did not significantly affect other
parameters during study period. There were no serious adverse events reported and the proportion of
patients experiencing adverse events was similar between the two groups.
Interpretation and conclusions: Modest reduction in serum free T3 levels in the isoflavone group in the
absence of any effect on other thyroid parameters might be considered clinically unimportant.
Key words Isoflavones - menopausal symptoms - oophorectomised women - phytoestrogens - thyroid autoimmunity - thyroid function
outweigh the benefits. In order to address the health
concerns with HRT, there is a growing interest in the
natural alternatives to HRT. Phytoestrogens, a class
of several different chemicals produced by a variety
Indian J Med Res 133, June 2011, pp 633-640
634 INDIAN J MED RES, JuNE 2011
of plants, possess demonstrable estrogenic activity.
They can act as selective estrogen response modulators
(SERMs) since they have measurable affinity for
estrogen receptors4. Of these, the soy isoflavones have
received considerable attention for development as
dietary supplements for post-menopausal women due
to absence of adverse effect profile of HRT.
harmful effects of soy isoflavones on thyroid
function. Earlier studies had reported development
of goiter in rats fed with soy5. It was earlier reported
that soy isoflavones caused increase in serum
thyroxine (T4)6 and triiodothyronine (T3)7 levels in
rodents. Schmutzler et al8 demonstrated inhibition of
iodide uptake and irreversible inactivation of thyroid
peroxidase (TPO) in an in vitro study employing rodent
tissue thereby indicating interference with thyroid
hormone biosynthesis at the level of iodide uptake
and organification by genistein, a soy isoflavone.
Subsequently, in 1950s and 1960s, cases of goiter
without overt signs of hypothyroidism were reported
in infants consuming soy based infant formula9.
Alterations in thyroid function with modified dietary
soy or isoflavones have also been reported in a few
studies in post-menopausal women10,11 , who are in
particular prescribed isoflavones as an alternative to
HRT. However, there is no prospective human study
to indicate the effect of soy isoflavones on thyroid
autoimmune status. Women with natural menopause
continue to synthesize and secrete small quantities
of estrone from the ovaries and estrogen is known to
cause elevation of thyroid binding globulin (TBG)12
hence the true interaction of isoflavones with thyroid
function needs evaluation in women with surgical
There is a concern, however, regarding the
widespread use of soy extracts as dietary supplements
or as prescription only drugs in different parts of the
world13, it was thought prudent to investigate in a
randomized, double blind, placebo controlled trial
whether soy isoflavones extract caused any significant
alterations in the thyroid profile of women undergone
Keeping in view the safety concerns related to the
Material & Methods
Subjects: All women who reported to the Obstetrics
and Gynaecology out patient department of Post-
graduate Institute of Medical Education and Research
(PGIMER), Chandigarh, India, from March 2007 to
January 2008 were screened for inclusion in the study.
Those who had undergone bilateral oophorectomy, were
less than 55 yr of age had baseline thyroid stimulating
hormone (TSH) values within the normal range and
were willing to comply with the protocol were included
in the study. They were excluded if any of the following
criteria were present: (1) suffering from any thyroid
disease, (2) suffering from any autoimmune disorder,
(3) already on isoflavones, (4) taken HRT/estrogen
replacement therapy (ERT) within previous 8 wk, (5)
presence of renal and/or hepatic disease, (6) active major
psychiatric disorders, (7) history of thrombophlebitis
or thromboembolism or cerebrovascular disorders,
(8) uncontrolled hypertension with blood pressure
> 180/100 mm Hg, (9) uncontrolled diabetes, (10)
were on any drug which can affect thyroid function,
(11) presence of active infection or malignancy, and
(12) present or past history of soy or nut related food
Ethics Committee and all the participating women
signed a written informed consent prior to enrollment
to the study. Eligible women were randomized so
that they had an equal probability of assignment to
either of the two groups. The randomization code
was developed using random number table to select
random permuted blocks of length four. The identity of
the drugs was hidden by packing in numbered opaque
envelopes to ensure concealment of the sequence
until assigned. Randomization, allocation sequence
generation and packing of envelopes were done by
investigators not directly involved in dispensing and
evaluating the treatments so that it was double blind
- both the patient and evaluating clinician not aware
of the assigned treatment. The participants remained
on the same allocation throughout the study period if
they continued. The randomization code was revealed
to the investigators once recruitment, data collection,
and laboratory analyses were complete.
The study protocol was approved by the Institutional
randomization (baseline) and at three weekly intervals
for 12 wk.
The participants attended the clinic at the time of
Study interventions: The participants were randomized
to either placebo or study drug to be administered
once a day orally for 12 wk. The study drug tablet
contained 75 mg of soy isoflavones standardized to
provide isoflavones 40 per cent (Genistein and Genistin
25%; Daidzein and Daidzin 15%) along with 200 mg
elemental calcium, 100 mg elemental phosphorus,
and 100 Iu of vitamin D3. Placebo tablet matching in
colour, size, shape and taste and containing identical
quantity of calcium, phosphorus and vitamin D3 was
used as control treatment. Patients were advised to
take one tablet daily at bedtime with 150 ml of plain
water for a total 12 wk period. All the patients were
instructed to avoid dietary phytoestrogen consumption
by avoiding soy, seeds and sprouts, beans and legumes
during the study period. Other treatments which might
interfere with thyroid function were also avoided
during the study. However, concomitant treatments
for other associated illnesses were allowed. Since the
drug is available in the market at the required dose,
drug product label instruction was followed for storing
and dispensing of the drug. Appropriate treatment
was provided for any observed adverse event. The
patients were provided with a contact phone number to
call in case of emergency. The patients were asked to
bring the drug envelopes during subsequent visits and
compliance was assessed by pill counting. More than
80 per cent compliance was considered as adequate.
isoflavones cause a significant alteration in thyroid
economy and autoimmunity in comparison to placebo
in euthyroid, surgical menopausal women. The primary
outcome of the study was complete serum thyroid
profile (TSH, free T3, free T4, Thyroid binding globulin
and anti – TPO antibodies). The secondary outcomes
included assessment of menopausal symptoms, serum
follicle stimulating hormone (FSH) and estradiol
In the present study the hypothesis tested was that
assessed at baseline, six wk and at study completion
(12 wk) while presence of any goiter was ruled out
by palpation of thyroid gland during each visit. The
assessment for serum FSH and estradiol was done at
baseline and 12 wk while menopausal symptoms were
assessed during each three weekly visit.
For each patient, the serum thyroid profile was
ml blood was withdrawn aseptically by venipuncture
from each patient at baseline (0 wk), six and 12 wk
after initiation of treatment. The blood samples were
allowed to clot at room temperature and centrifuged
at 1260 g for 10 min. The serum thus separated was
stored at -20˚C for further estimations. To reduce the
effects of interassay variability, all samples from each
subject were analysed in duplicate in the same batch.
Free T3 and free T4 were determined by single antibody
coated tube Radio-immuno assay (RIA) using 125I
labelled hormone (Roche Diagnostics, Indianapolis,
IN, uSA). TSH was determined by double antibody
RIA using 125I labelled hormone (Roche Diagnostics,
For the assessment of various parameters, about 10
Indianapolis, IN, uSA). Thyroid binding globulin
(TBG) and anti-TPO antibodies were determined
by electrochemiluminescence immunoassay using
specific antibodies labelled with a ruthenium complex
(Roche Diagnostics). Serum FSH was determined
quantitatively by chemiluminescence immunoassay
in vitro which employs two different monoclonal
antibodies specifically directed against human FSH.
Radioimmunoassay was used to estimate serum
estradiol levels (reference range in postmenopausal
women 70-190 pmol/l).
done by calculating the menopause symptom score
for each patient using Menopause rating scale
(MRS)14. The total score of MRS ranges between 0
(asymptomatic) to 44 (highest degree of severity).The
score increases point by point with increasing severity
of subjectively perceived complaints in each of the 11
items (severity expressed as 0-4 points in each). The
various symptoms included in questionnaire were -
psychological symptoms - 0 to 16 points (4 symptoms:
depressed, irritable, anxious, exhausted); somato-
vegetative symptoms – 0 to 16 points (4 symptoms:
sweating/flash, cardiac complaints, sleeping disorders,
joint and muscle complaints); and urogenital symptoms
– 0 to 12 points (3 symptoms: sexual problems, urinary
complaints, vaginal dryness). The composite scores for
each of the dimensions (sub-scales) is based on adding
up the scores of the items of the respective dimensions.
The composite score (total score) is the sum of the
The assessment of menopausal symptoms was
health status by routine clinical examination and
appearance of any adverse events during each visit.
The participants were also assessed for general
Sample size: The normal range of TSH is 0.5-5.5
micro IU/ml (3± 2.5). Considering a change of 2.5
micro Iu/ml from baseline to the end of follow up to
be clinically significant in isoflavone arm over placebo
and assuming a SD of 2.5 at alpha of 5 per cent and
power of 80 per cent, 16 patients were required in each
group; thus needing a total of 32 patients. Expecting 60
per cent compliance, it was decided to include up to 54
patients in the study.
Statistical analysis: Data were expressed as mean ± SD
unless specified, numbers (percentages) and median
(interquartile range). Proportions were compared using
chi-square tests with continuity correction or Fisher’s
exact test when appropriate. The between and within
groups repeated measurements of outcomes were
MITTAL et al: ISOFLAVONES ON THYROID FUNCTION IN OOPHORECTOMISED WOMEN 635
analysed using Generalized linear models- Repeat
measures and Repeated measures analysis of variance,
respectively. Also, mean change from baseline in various
parameters between the two groups was compared
using unpaired Student’s t test with Welch correction
for parametric data or Mann whitney u test for non
parametric data. Two sided significance tests were used
throughout. P<0.05 was considered significant.
underwent screening. Of these, 43 underwent
randomization, with 21 and 22 assigned to the isoflavone
and placebo groups respectively (Fig.). In the isoflavone
group, one patient withdrew consent later on due to
non specific reasons and one discontinued treatment
because of adverse effects. In the placebo group, two
patients discontinued treatment due to adverse effects.
Two patients in isoflavone group and three patients in
placebo group were lost to follow up and could not be
contacted. Hence, 17 patients in each group completed
A total of 77 women with bilateral oophorectomy
intention to treat (ITT) principle and all patients for
The primary analysis was done by modified
whom at least one blood sample for estimation was
available after treatment allocation were included in
the analysis. For thyroid parameters, the total number
of missing values were three in isoflavones group
and five in placebo group. The primary analysis for
all outcomes was done by last observation carried
forward principle. For primary outcomes, an additional
sensitivity analysis was carried out by replacing the
missing values with least and highest values for the
respective patient and results compared.
in terms of age, body mass index, time since surgery
(bilateral oophorectomy), past use of HRT, co-existing
and past medical history (Table I). The most common
At baseline, the two study groups were similar
Fig. The CONSORT diagram for flow of participants.
Table I. Demographic profile and clinical characteristics of patients
in isoflavone and placebo groups at baseline
(n = 21)
49.14 ± 6.83
24.99 ± 4.58
(n = 22)
46.28 ± 6.14
24.94 ± 4.03
Age, yr (mean ± SD)
BMI, kg/m2 (mean ± SD)
Time since oophorectomy, in
months; median (IQR)
Past HRT use, n (%)
Coexisting illness, n (%)
Type 2 diabetes
Past history, n (%)
Thyroid profile (Mean ± SD)
Free T3 (pM/l)
Free T4 (pM/l)
Menopause symptom score
(mean ± SD)
Serum FSH (m Iu/ml)
(mean ± SD)
Serum estradiol (pmol/l)
3 (14.3)1 (4.5)
4.05 ± 0.36
13.88 ± 1.90
1.87 ± 1.14
16.68 ± 7.34
42.06 ± 68.38 98.25 ± 173.90
12.47 ± 8.15
4.21 ± 0.57
13.45 ± 2.25
2.04 ± 1.61
19.56 ± 6.97
11.53 ± 6.18
5.64 ± 3.92
4.94 ± 3.39
1.88 ± 1.69
80.42 ± 32.71 77.24 ±26.92
6 ± 3.37
4.41 ± 3.34
1.12 ± 1.45
110 (110-110) 110 (110-135)
BMI, body mass index; IQR, interquartile range; HRT, hormone
replacement therapy; T3, triiodo-thyronine; T4, thyroxine; TSH,
thyroid stimulating hormone; TBG, thyroid binding globulin; TPO,
thyroid peroxidase; FSH, follicle stimulating hormone
636 INDIAN J MED RES, JuNE 2011
cause of surgery in both the groups was fibroid uterus
(Table II). Three patients in the isoflavones group and
one patient in the placebo group had taken HRT in the
past on account of post-hysterectomy or complaints of
menorrhagia. The duration of HRT ranged from two
months to five years but all the patients had stopped
the intake of HRT between 6 to 48 months prior to
enrolment to the present study.
isoflavone and placebo groups is depicted in Table III.
None of the parameters showed significant alteration
with time in isoflavone group compared to placebo.
However, there was a statistically significant change in
free T3 levels within isoflavone group. At baseline, four
patients in the isoflavone group and five in the placebo
group had levels of anti-TPO antibodies higher than
the normal range (>34 Iu/ml), of whom three patients
in each group exhibited further increase in antibodies
levels at 12 wk. There was a decrease in antibody
The alterations in thyroid profile with time between
levels from baseline in one patient in each group
though the levels remained above the normal range
and in one patient in placebo group, antibody levels
declined to normal (6.5 Iu/ml) from baseline value of
36.1 Iu/ml. Of the patients having normal antibodies
levels at baseline, one patient in placebo group showed
an increase in levels (40.19 Iu/ml at 12 wk) from
baseline value (9 Iu/ml) while in the remaining the
levels remained well in the normal range during the
study period (Fisher’s exact test for between groups,
P=0.99). The results of the sensitivity analysis for all
the parameters were similar to the primary analysis.
wk was recorded and change in the score with time
between two groups compared (Table IV). There was no
significant change in the score with time in isoflavones
group compared to placebo. When the mean change at
12 wk in various subscores was compared separately
between two groups, a significant improvement in
urogenital symptoms was seen with isoflavones as
compared to placebo (Table V). The mean change in
serum FSH and estradiol levels at 12 wk from baseline
in two groups was not statistically significant from
each other (Table V).
MSS for each patient at baseline, 3, 6, 9 and 12
isoflavone group discontinued treatment after 4 wk
because of disturbed sleep, anxiety and restlessness.
In the placebo group, two of the 22 patients (5%)
experienced adverse effects in the form of generalized
bodyaches and increased fatiguability and they
discontinued treatment at 2 wk and 2 days respectively.
The proportion of patients experiencing adverse events
was similar between two groups.
One of the 21 women enrolled (2%) in the
T3 levels was observed in isoflavone group. Isoflavone
In the present study, a significant change in free
Table II. Comparison of causes of bilateral oophorectomy in
isoflavones and placebo groups
Dysfunctional uterine bleeding
Post menopausal bleeding
Broad ligament fibroid
Complete hydatidiform mole
Mass lower abdomen
Table III. Comparison of changes in thyroid profile with time between isoflavone and placebo groups
Parameter Isoflavone group (n=21)Placebo group (n=22)
P value for Time*
0 wk 6 wk 12 wk
0 wk6 wk 12 wk
Free T3 (pm/l)
Free T4 (pm/l)
4.05 ± 0.36 4.12 ± 0.693.76 ± 0.55 0.02* 4.21 ± 0.574.12 ± 0.314.07 ± 0.430.530.46
13.88 ± 1.9013.88 ± 2.09 13.61 ± 1.390.77 13.45 ± 2.2513.35 ± 1.50 13.55 ± 1.54 0.920.28
1.87 ± 1.141.50 ± 0.833.28 ± 3.010.082.04 ± 1.61 1.83 ± 1.352.72 ± 3.720.56 0.55
TBG (Iu/ml)16.68 ± 7.3415.81 ± 5.5016.17 ± 7.180.9219.56 ± 6.9718.49 ± 9.21 17.31 ± 8.33 0.510.93
42.06 ± 68.38 61.42 ± 143.71 63.75 ± 144.05 0.5698.25 ± 173.9 134.58 ± 242.72131.53 ± 240.370.80 0.74
Values expressed as ,mean ± SD. Within group analysis done by Repeat Measures ANOVA. Between group analysis for Time*Group interaction done by Generalised
Linear Models- Repeated Measures
MITTAL et al: ISOFLAVONES ON THYROID FUNCTION IN OOPHORECTOMISED WOMEN 637
group also demonstrated an improvement in urogenital
symptoms compared to placebo.
has been seen in women due to increase in TSH levels
with advancing age15. In this study, at the time of
screening, about 18 per cent of women were suffering
from thyroid disease. Different studies in rodents
have also documented the effect of soy isoflavones on
Increased prevalence of subclinical hypothyroidism
isoflavones interact with thyroid gland have been
hypothesized. These include interference with
enterohepatic circulation of thyroxine17, competition
with thyroid hormones for thyroid sulfotransferase
enzymes18, inhibition of thyroid peroxidase19 and
interference with thyroid hormone synthesis by
inhibition of iodide uptake and organification8.
Besides, isoflavones lead to immune dysfunction by
causing potent stimulation of T cell and B cell mediated
immunity due to induced structural changes in thyroid
A number of potential mechanisms by which
a decline in free T3 levels with high iso diet. Another
study conducted in post-menopausal
demonstrated a rise in T4 with 56 mg isoflavones/day
and a rise in T3 and TSH with 90 mg isoflavones/day
at 6 months compared with controls but the alterations
were considered clinically non-significant10.
A study in premenopausal women21 demonstrated
changes in thyroid profile with isoflavones in
menopausal women11, 22, 23. The precise reason for such
reported variations is unclear although differences in
doses, dosage forms, isoflavone composition or the
duration of treatment might be an important factor.
Several other studies revealed non significant
Menopause rating scale was also assessed, which is
a validated scale to detect the severity of menopausal
symptoms24,25. A significant reduction in urogenital
subscore was observed with isoflavones. No observed
benefit on hot flushes might partially be explained by
a rise in FSH levels with isoflavones. Previous studies
also report variable results26-28.
In the present study, the effect of isoflavones on
decreasing peripheral aromatization of androgens10,11
and inhibiting aromatase activity in preadipocytes29.
An absence of such a finding in the present study might
be due to inadequate sample size as the study was not
powered to detect the same.
Isoflavones cause a reduction in estradiol levels by
menopause were taken and not natural menopausal
women as some amount of estrone is produced by
ovary even after menopause and they are not estrogen
null in true sense and hence the need to ameliorate
the possible interaction between endogenous estrogen
and thyroid function, as estrogen causes an elevation
of thyroid binding globulin levels12. Also, we studied
the effect of isoflavones on thyroid autoimmunity by
quantitative estimation of anti-TPO antibodies, which
was not done in previous clinical studies.
In the present study, women with surgical
The study did not measure isoflavonoids in blood
or in urine. Pharmacokinetic data for isoflavones
would have provided an opportunity to ascertain
the compliance and bioavailability and understand
the kinetic – dynamic correlation for the agents.
Secondly, it was a fixed dose study for a limited
duration, whereas the postmenopausal women
consume soy products over prolonged periods of
time. Currently, there are no specific guidelines
available to justify a particular dose or a particular
There were a few limitations in the present study.
Table IV. Comparison of change in Menopause Symptom Score
(MSS) with time between isoflavone and placebo groups
Time (wk)Menopause symptom score
0 12.47 ± 8.15
3 12 ± 7.45
6 10.12 ± 6.91
9 9.35 ± 5.23
12 9 ± 5.14
11.53 ± 6.18
11.94 ± 6.12
11.18 ± 5.41
10.59 ± 5.37
11 ± 6.96
Values are expressed as mean ± SD. Between group analysis done
by Generalized Linear Models- Repeated Measures. P= 0.15
Table V. Comparison for mean change in various subscores of
Menopause Symptom Score (MSS), serum FSH and estradiol at
12 wk from baseline between isoflavone and placebo groups
Psychological -2.29 ± 3.93
Somatovegetative-0.47 ± 2.83
urological-0.71 ± 1.16
Serum FSH (mIu/ml) 12.82 ± 40.32
-1.0 ± 2.65
0.12 ± 1.49
0.41 ± 1.73
7.68 ± 33.74
7.06 ± 43.09
0.99 -2.65 ± 35.09
Values expressed as mean ± SD; Comparisons for psychological,
somatovegetative subscores and serum FSH done by unpaired
Student’s t test and for urogenital subscore and serum estradiol,
Mann-Whitney u test was used
638 INDIAN J MED RES, JuNE 2011
composition of soy isoflavones to offer greater
benefit as compared to the risk to the postmenopausal
women. The use of active comparator in the form
of synthetic HRT would have been more justified
but in view of risks associated with HRT as
highlighted in Women’s Health Initiative report,
20021 and consequent declining trend towards HRT
prescription, we preferred to use placebo control.
The dietary intake of soy in the participants prior
to enrolment in the study was not estimated which
could have a possible influence on the results. Also,
iodine status was not evaluated in study subjects as
there remains a theoretical concern based on in vitro
and animal data that soy may increase the risk of
clinical hypothyroidism particularly in individuals
whose iodine intake is marginal30.
present study that at 75 mg per day, isoflavones are
relatively innocuous in terms of thyroid functional
status. However, one needs to exercise caution in
advocating these agents to women who might be
iodine deficient. Also, isoflavones can be beneficial
for relief of menopausal symptoms with variable
effect on different components of this symptom
In conclusion, it might be inferred from the
for providing the study drugs.
Authors thank Dr Reddy’s Laboratories Ltd, Hyderabad, India
of hormone replacement therapy after the report from the
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and Research, Chandigarh 160 012, India
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