Original Article
Free access
- DOI:
- 10.3109/13685538.2015.1135323
pages 134-142
- Received: 24 Sep 2015
- Accepted: 19 Dec 2015
- Published online: 20 Jan 2016
Abstract
This study examined the effect of Testofen, a specialised Trigonella foenum-graecum
seed extract on the symptoms of possible androgen deficiency, sexual
function and serum androgen concentrations in healthy aging males. This
was a double-blind, randomised, placebo-controlled trial involving 120
healthy men aged between 43 and 70 years of age. The active treatment
was standardised Trigonella foenum-graecum seed extract at a dose
of 600 mg/day for 12 weeks. The primary outcome measure was the change
in the Aging Male Symptom questionnaire (AMS), a measure of possible
androgen deficiency symptoms; secondary outcome measures were sexual
function and serum testosterone. There was a significant decrease in AMS
score over time and between the active and placebo groups. Sexual
function improved, including number of morning erections and frequency
of sexual activity. Both total serum testosterone and free testosterone
increased compared to placebo after 12 weeks of active treatment. Trigonella foenum-graecum
seed extract is a safe and effective treatment for reducing symptoms of
possible androgen deficiency, improves sexual function and increases
serum testosterone in healthy middle-aged and older men.
Related article
introduction
Testosterone concentrations decrease in men at a rate of 1–2% per year after the age of 40 [1–3].
This decrease varies considerably between individuals, relates to the
accumulation of co-morbid conditions including weight gain [4–6]
and may be due to a combination of reduced hypothalamic gonadotropin
releasing hormone outflow, alterations in androgenic negative feedback
and decreased responsiveness of testicular tissue [7,8].
This decline in testosterone is associated with decreased albumin and
increased sex hormone binding globulin (SHBG), resulting in higher
levels of serum testosterone binding to SHBG, which together decreases
free (bioavailable) testosterone [9].
The clinical significance of a low or low-normal testosterone level in men is not well understood [10].
There is an association between decrease in serum testosterone in older
men with reduction in sexual activity and desire, although causality is
as yet undetermined [11].
There is also evidence that lower testosterone levels are linked with
an increased risk of developing metabolic syndrome and cognitive decline
[12,13].
In addition, other symptoms of deficiency may include muscle weakness,
weight gain, increased abdominal fat, musculoskeletal changes and joint
pain, hot flushes or sweating, sleep disturbances, insomnia, fatigue,
depression, decreased body hair and skin alterations, and low bone
mineral density. Depending upon the set of symptoms being experienced, a
negative effect on quality of life as well as an impact on health and
relationships may occur [14,15].
Testosterone
also decreases in response to age-related physical changes such as
weight gain, increased waist circumference and deterioration of general
health associated with chronic disease such as diabetes, liver disease,
and cardiovascular disease [16,17].
Medications such as opioids, glucocorticoids and anti-depressants may
directly inhibit the hypothalamic-pituitary-testicular axis also
resulting in decreased testosterone [18–20].
The
combination of low testosterone and the array of the above symptoms is
variably referred to as aging male syndrome (AMS), andropause, partial
androgen deficiency of the aging male (PADAM), and late-onset
hypogonadism (LOH) [15,21,22]. The prevalence is unknown, large-scale studies suggest it may be as little as 2.1% in men aged 40–70 [23,24] but other clinical studies have reported that androgen deficiency affects 39% of men aged greater than 45 years [25].
Currently,
testosterone replacement therapy is prescribed to men when they are
clinically defined as androgen deficient. Testosterone replacement in
men with established hypogonadism significantly increases lean body mass
and decreases fat mass without an overall change in body weight and
improves sexual function and cognition [15,26–28].
Overall, there are few large-scale clinical trials on the efficacy of
testosterone therapy in the older male age group. Some studies suggest
there are potential health risks including erythrocytosis and prostate
cancer [22,29] while others have shown some beneficial, though short-lived effects [30].
There
is limited research on the use of herbal medicines to improve male
health, particularly to increase testosterone levels and support healthy
sexual function. To date, there are no published human clinical studies
using herbal medicines for symptoms associated with the age related
decrease in androgens.
Earlier research suggested that Trigonella foenum-graecum seed extract had a positive effect on sexual health and quality of life [31], as well as demonstrating anabolic and androgenic activity in younger men [32].
It is thought that this positive effect was, at least, partly, due to
increased testosterone, including free testosterone and that Trigonella foenum-graecum
seed extract may also be an effective treatment for the symptoms of
possible androgen deficiency in aging men. The basis for this androgenic
activity may be due to the fact that Trigonella foenum-graecum
seeds contain soluble steroidal saponins, specifically furostanol
glycosides responsible for complexing cholesterol in the cell membrane [33,34]. Other studies that have shown that Trigonella foenum-graecum increases testosterone, and free testosterone suggest it may be an incomplete 5-alpha reductase and aromatase inhibitor [35].
The hypothesis was that the use of Trigonella foenum-graecum
seed extract for 12 weeks as a therapy would reduce the symptoms of
possible androgen decline, improve reported sexual function and increase
serum testosterone in healthy middle-aged and older males.
Methods
Study design
This
was a single-site, double-blind, randomised, short-duration (12 week)
clinical trial utilising active and placebo arms to assess (i) the
factors that influence testosterone concentrations and (ii) the effect
of Trigonella foenum-graecum seed extract on symptoms of possible
androgen deficiency, sexual function and serum hormone concentrations,
particularly testosterone, in healthy aging males. It was conducted
between February and November 2014 in Brisbane, Australia.
Study population
The
study population included 120 healthy male subjects, aged 43–75 years,
recruited through a trial recruitment database and public media. After
preliminary screening via telephone, subjects were required to attend a
pre-trial interview and provide written informed consent. Comprehensive
screening was performed after an initial health assessment including
lifestyle questions, current medications, medical history and a physical
examination.
Potential subjects were
excluded if they had any of the following: any condition which in the
opinion of the investigator made the subject unsuitable for inclusion,
diagnosed erectile dysfunction or any physical disability that may limit
sexual function, had received any treatment/therapy (including
testosterone or anabolic steroids) for any sexual disorder during last 6
months, were being prescribed anticoagulation therapy, were receiving
levodopa for Parkinson’s disease or calcipotriene for psoriasis, were
diagnosed with severe renal and/or hepatic insufficiency, were diagnosed
with genital anatomical deformities, uncontrolled diabetes mellitus,
had a history of spinal cord injury, major psychiatric disorder, and/or
had any abnormal secondary sexual characteristics. They were also
excluded if they were diagnosed with prostate cancer or benign prostatic
hypertrophy, had an acute genitourinary disorder or history of genital
surgery, if they had a current or past history of chronic alcohol and/or
drug abuse or had a suspected or diagnosed chickpea allergy. If a
potential subject was currently participating in another trial or had
been in any other clinical trial during last 30 days they were also
excluded from the present study.
Outcomes
Primary
Symptoms of possible androgen deficiency
The primary outcome measure was efficacy of treatment for symptoms using the Aging Male Symptom (AMS) questionnaire [36].
It consists of 17 questions in 3 sub-scales, psychological, somatic and
sexual. These sub-scales as well as the total score were used to assess
symptoms. Subjects completed the questionnaires pre-trial (baseline
data), upon completion of weeks 6 (mid-trial) and 12 (completion).
Secondary
Sexual function
Sexual
function was assessed using the Derogatis Interview for Sexual
Functioning-Self Report (DISF-SR) questionnaire at baseline and week 12
(completion). It was designed to measure the quality of sexual function.
The DISF-SR is a set of 21 questions, with 4 sub-domains: sexual
fantasy (SC), sexual arousal (SA), sexual behaviours (SB) and orgasm (O)
[37].
The DISF-SR Sexual sub-domain asks specifically about the frequency of
morning erections and the Sexual Drive/Relationship sub-domain contained
a question regarding the frequency of sexual intercourse.
Serum sex hormone concentrations
Secondary outcomes included serum total and calculated free testosterone (Sodergard equation, [38]),
sex hormone binding globulin (SHBG), DHEA-S, androstenedione,
oestradiol and prolactin. The subjects had blood drawn in the morning
after an overnight fast at baseline, 6 weeks (mid-trial) and 12 weeks
(completion). Analysis was conducted at Queensland Medical Laboratories
(QML), Brisbane, Australia by chemiluminescent immunoassay (CLIA).
Other outcomes
Sleep quality was assessed using the Pittsburgh Sleep Index (PSI) [39].
The Multi-dimensional Fatigue Index (MFI-20) was used to assess
fatigue. The MFI-20 provides a total score for fatigue and also includes
the individual domains of general, emotional, physical, mental health
and vigour as separate aspects to fatigue [40]. Physical activity was measured using the International Physical Activity questionnaire (IPAQ) [41].
Other
physical health parameters and anthropometric measurements (weight,
height, waist, hip, grip strength) were also performed. Red and white
blood cells, electrolyte and liver function and lipid profile were also
measured at baseline and 12 weeks.
Randomisation and blinding
Randomisation
of the products was performed independently of the investigators using
Random Allocation Software, version 1.0, May 2004. The investigational
products were delivered to the investigators in trial product containers
that were identical in function and appearance, marked from 001 to
0120. Once enrolled in the trial, subjects were randomly allocated to
the next available number in the sequence, either the placebo comparator
group (n = 60) or the active intervention group (n = 60).
Investigators were blinded to the randomisation and therefore blinded
to which subjects were allocated to the active and treatment arms.
Subjects
were monitored for compliance with the protocol by a combination of
telephone and email communications. The doses taken were assessed by
number of returned tablets at completion of the study.
Statistical methods
Sample size
Sample
size was calculated on the primary outcome, the AMS total score. Based
on a power of 80%, a sample size of 48 subjects in each treatment group
was required, with 60 subjects recruited to account for potential
withdrawals.
Analysis
The
primary outcome endpoint (AMS questionnaire total and domain scores) at
baseline, week 6 and week 12 was analysed using a two way repeated
measures ANOVA for treatment and time. The DISF-SR total and domain
scores were assessed for statistical difference within-groups (change
from baseline) and between groups by t-tests. Change in pathology
data was analysed with ANCOVA using the covariates of BMI and age. The
correlations were calculated using the Pearson Correlation Co-efficient.
Effect sizes are reported as Eta squared (η2).
The
study was carried out according to the principles expressed in the
Declaration of Helsinki and was approved by the Queensland Clinical
Trials Network Human Research Ethics Committee (QCTN) No: 2013002. The
trial was registered with the Australian New Zealand Clinical Trials
Registry (ANZCTR) No: 12613000925741.
Results
Demographics
Initially,
120 men were enrolled and commenced treatment in the study, with 111
completing the study; 55 in the active treatment group and 56 in the
placebo group (Figure 1).
There were no significant differences between the active treatment and
placebo groups for age, anthropometric measures and the lifestyle
factors (Table 1). All men had a sexual partner for the duration of the study.
Table 1. Subject demographics at baseline.
Total
cholesterol, triglycerides, LDL and HDL were not significantly
different between the two groups. All men had normal full blood count,
renal and liver function and prostate specific antigen (PSA) levels
within healthy reference range for their age. The mean serum total
testosterone and free testosterone concentrations represented the lower
end of the healthy reference range for men in this age group (Table 1).
Relationship between age, BMI and health indices
There
was no correlation between age and total testosterone although there
was a weak negative correlation between age and free testosterone (r= −0.196, p= 0.042). A negative correlation was found between BMI and both total testosterone (r= −0.304, p = 0.001) and free testosterone (r= −0.279, p = 0.003). Total testosterone was positively correlated with HDL cholesterol (r = 0.237, p
= 0.017) but not with total or LDL cholesterol. There was no correlation
between testosterone and the AMS score except on the somatic sub-domain
(r= −0.310, p = 0.001). There was no correlation between
total or free testosterone, sexual function (measured by the DISF-SR),
sleep or physical activity in this group of men.
Treatment with Trigonella foenum-graecum seed extract
Effect on general health parameters
There
was no change in BMI, waist/hip ratios or grip strength during the
course of the study for either the active treatment or the placebo
groups (Table 2).
Table 2. Anthropometric parameters in the active treatment and placebo groups at baseline, week 6 and week 12.
There
were no significant changes in sleep patterns, the type or duration of
physical activity or fatigue score in either the active treatment or the
placebo group.
Effect on symptoms of possible androgen deficiency
The
mean AMS total score and subscores for the active and placebo treatment
groups at baseline, 6 weeks and 12 weeks are shown in Figure 2. There was no significant difference between the groups at baseline.
Repeated measures ANOVA showed a significant difference across time F(2,216) = 8.6, p < 0.001, η2 = 0.073 and a significant difference between groups F(1,108) = 6.4, p = 0.013, η2 = 0.056 for total AMS Score.
There were also significant differences for the somatic and sexual sub-scores across time F(2,216) = 9.1, p < 0.001, η2 = 0.078 and F(2,216) = 6.3, p = 0.002, η2 = 0.055 respectively and between treatment groups F(1,108) = 4.8, p = 0.03, η2 = 0.043 and F(1,108) = 7.1, p = 0.009, η2 = 0.062. There was a significant difference across time for the psychology sub-score F(2,216) = 4.9, p < 0.008, η2 = 0.043 but no treatment effect F(1,108) = 2.6, p < 0.11.
Effect on sexual function
The effect of Trigonella foenum-graecum
seed extract on sexual function was assessed using the DISF-SR at
baseline and at week 12. There was a significant change in the total
score in active treatment group (p = 0.006) after treatment. Analysis of the sub-domains showed a significant difference in the sub-domains of Sexual Arousal (p = 0.001) and Sexual Drive/Relationship (p
= 0.007), but there were no changes in the sub-domains of Sexual
Cognition, Sexual Behaviour or Orgasm. There were no changes observed in
the placebo group before or after treatment in the total score or any
sub-domain (Table 3).
Table 3. Assessment of changes in sexual function in active treatment group and placebo group at baseline and 12 weeks.
At baseline, both groups reported an average of one erection per week but this increased significantly to 2–3 per week (p
= 0.001) in the active treatment group. At baseline, both groups
reported sexual activity of approximately 1–2 times per month, this
increased significantly to almost once a week (p = 0.004) in the
active treatment group by week 12. These results were consistent with
the positive results reported in the sexual function sub-domain of the
AMS questionnaire “Which of the following symptoms apply to you at this
time”, in particular, questions 16 “Decrease in the number of morning
erections” and question 17 “Decrease in sexual desire/libido” (Figure 3).
Effect on sex hormones, liver function and lipids
The
results of this study showed that there were no changes in levels of
DHEA-S, androstenedione, oestradiol, SHBG or prolactin in either group
during the 12 weeks of the study (Table 4).
There were no significant changes in liver function, total, LDL or HDL
cholesterol, or triglycerides, in either group after 12 weeks.
Table 4. Hormone levels for active treatment and placebo groups at baseline, week 6 and week 12.
Total
testosterone levels were similar between both groups at baseline. There
was a small but significant difference in the change from baseline (Δ)
values between the active treatment and placebo groups for testosterone
and calculated free testosterone at week 12. Further, bivariate analysis
of covariance was calculated with a Bonferroni adjustment using BMI and
age as the covariate factors and both total testosterone F(1,91) = 13.8, p < 0.001, η2 = 0.134 and free testosterone F(1,91) = 10.8, p = 0.002, η2 = 0.106 remained significant (Table 4).
Safety data
The
routine hematological and biochemical parameters were similar at
baseline and after 12 weeks of treatment. The treatment was well
tolerated. There were no serious adverse effects. There were five minor
adverse reactions reported, three in the active treatment group
(increased frequency of headaches (2), dizziness (1) and two in the
placebo group (nausea (1), increased asthma symptoms (1), however these
may not have been attributed to the treatment.
Discussion
This is the first published study of a Trigonella foenum-graecum
seed extract in the treatment of symptoms of possible androgen
deficiency in aging men. Symptom severity was measured by the aging
males symptoms scale (AMS), which was developed as an indication of the
severity of symptoms [42]. The results of this study demonstrate that Trigonella foenum-graecum
(Testofen) seed extract significantly reduces symptom severity in the
aging male. The most significant changes observed were in the somatic
and sexual function domains of the AMS.
Sexual
function was also assessed using the DISF-SR sexual function
questionnaire, and this was found to compare well with the sexual
function domain of the AMS questionnaire. It showed that treatment with Trigonella foenum-graecum
seed extract resulted in a significant improvement in sexual
functioning, including desire, arousal and frequency of morning
erections. These results are supported by an earlier study of younger
men using the same Trigonella foenum-graecum seed extract which was found to have a positive effect on sexual function in men who were experiencing low libido [31].
Furthermore, this study has demonstrated that this particular Trigonella foenum-graecum
seed extract results in small but statistically significant increases
in serum total and free testosterone. This effect was independent of
age, as increases were observed in all age brackets from 40 years to 70
years. These results provide a potential mechanism for the positive
effects on somatic and sexual function observed in this study. It is
hypothesised that the reduction in severity of symptoms and increased
somatic and sexual function was directly or indirectly related to the
increased serum testosterone.
This is supported by an earlier study of another extract in younger exercising men that demonstrated that Trigonella foenum-graecum decreased body fat and increased total and free testosterone [32]. Potential mechanisms by which Trigonella foenum-graecum
may increase serum testosterone includes stimulation of pulsatile
GnRH/LH, increased testicular sensitivity to LH, and increased
testosterone synthesis or reduced testosterone catabolism. However,
further study still needs to be undertaken before a comprehensive
mechanism of action can be proposed.
A
similar pattern of reduced symptoms and improved sexual function is also
observed in men treated directly with testosterone. Behre et al. [15]
demonstrated that 6 months treatment with testosterone in men with low
serum total testosterone (< 15.0 nmol/L) and bioavailable
testosterone (6.68 nmol/L) and symptoms of androgen deficiency (using
the same AMS scale) resulted in progressive improvement in quality of
life as well as an improvement in lean body mass and decreased fat mass.
This is also supported by a more recent study using testosterone in men
aged 50–65 years for 24 months, where the AMS questionnaire was used to
show a marked improvement in the items related to sexual function and
mood, as well as significant improvements in both total and free
testosterone after 3 months, and an increase in lean muscle and decrease
in fat mass by 12 months. Interestingly, as seen with this study as
well, SHGB levels remained relatively unchanged, despite the increased
testosterone levels [9].
It is also supported by previous research indicating that serum free
testosterone is significantly correlated with the libido, erectile, and
orgasmic function domains on International Index of Erectile Function
(IIEF) questionnaire [43].
While
the AMS score consists of age-related and testosterone-associated
decline in health parameters in males, it has been considered as a
potential predictor of androgen status in men. Previous research had
found a significant correlation of AMS scores with lowered free
testosterone [44,45].
However, a number of other studies failed to reveal a correlation of
the questionnaire results with serum testosterone levels [46,47]. A recent study by Zengerling et al. [48]
demonstrated that AMS total score is not a predictor of total or free
testosterone levels or hypogonadism but there was a correlation with the
sexual and somatic sub-scores, a result that was also observed in this
current study. This suggests that the changes in testosterone, while
linked to sexual function and mood in men, is not responsible for all
aspects of aging.
There was only a weak
correlation between free testosterone levels and age. Instead, total
testosterone levels and free testosterone levels were inversely related
to BMI. This is consistent with recent studies indicating that in
generally healthy men, there was no decrease in the mean total
testosterone level with increasing age, yet statistically and clinically
negative correlation between testosterone and BMI and positive
correlation between testosterone and fitness [49].
While it has been suggested that there is an age-related decline in
testosterone due to altered function both centrally (at the level of the
hypothalamic-pituitary unit) and at the level of the testis [8],
other data indicate that the decline in testosterone is more associated
with the accumulation of co-morbidities, particularly weight gain [4–6].
The EMAS study of 3320 men aged between 40 and 79 years, showed that
the aging-related decline of testosterone has great inter-individual
variability, with about 20% of men over 60 years having serum
testosterone in the upper normal range of young men, and about 20% being
below the reference range. This research has also established that
testosterone in a man with BMI >30 is, on average, 30% lower than that of a man with BMI <25, at any age, which is more than the purely age-dependent decrease between 40 and 80 years [50].
The increase in serum testosterone observed across our study in the
active treatment group occurred independently of any change in BMI.
Neither
AMS nor serum testosterone was correlated with regular exercise (deemed
more than 3 days per week). Interestingly, a previous study on a larger
population of 421 men had shown that psychological, somatic and general
scores symptoms, as well as their severity were lower among those
subjects who reached the current recommendations for physical activity
during leisure and commuting time [51].
The
MFI scale was used to assess individual components of fatigue including
physical fatigue, mental fatigue, motivation and activity. As with
physical activity, there were no changes in fatigue noted as a result of
the treatment. The smaller sample size, time frame and possibly the
subject age group may have been limitations to observing any
differences. Earlier studies with testosterone gel have shown that sex
hormone levels, physical complaints, depression, sexuality and life
satisfaction, and low total and free testosterone are associated with
reduced motivation [52] and in an observational 6 month study using testosterone gel, significant improvements in fatigue scores were observed [53].
Furthermore,
in this study cohort, testosterone levels were positively correlated
with HDL cholesterol. There were no changes observed in other hormones,
DHEA-S, androstenedione, oestradiol or liver function after treatment
with Trigonella foenum-graecum seed extract. The herbal medicine
was well tolerated, although was associated with headache in <5% of
subjects, an effect also observed in the earlier study [31].
Recommendations have been published for the diagnosis, treatment and monitoring of hypogonadism in men [54].
In this document, a relatively high threshold for total testosterone of
<12.1 nmol/L was suggested to classify hypogonadism. Further
long-term studies are awaited to establish clear indications for and
long-term safety of testosterone therapy in men with low or borderline
testosterone concentrations in the absence of organic
hypothalamic-pituitary or testicular pathology [8]. The use of herbal medicine such as extract of Trigonella foenum-graecum
which has in this study shown efficacy in improving symptoms, may
become an alternative for symptomatic men where low or borderline
testosterone is associated with obesity, chronic disease and mood
disorder rather than organic hypothalamic–pituitary–testicular axis
pathology. However, further studies are needed to establish its
long-term safety and efficacy.
In conclusion, this extract of Trigonella foenum-graecum
seed was shown to be safe and effective, reducing symptoms of possible
androgen deficiency, improving sexual function and increasing serum
testosterone in healthy middle-aged and older men.
Trial registration
The
trial was registered with the Australian New Zealand Clinical Trials
Registry (ANZCTR) with Trial ID. ACTRN No: 12613000925741 and can be
accessed on the ANZCTR website.
Acknowledgements
We would like to thank Queensland Clinical Trials Network (QCTN) for providing the ethics committee review.
Declaration of interest
The investigational products and funding were supplied by Gencor Pacific, Hong Kong.
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