Download Effects of Tramadol on Fertility Hormones (Follicle Stimulating

British Journal of Medicine & Medical Research
14(8): 1-11, 2016, Article no.BJMMR.24620
ISSN: 2231-0614, NLM ID: 101570965
SCIENCEDOMAIN international
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Effects of Tramadol on Fertility Hormones (Follicle
Stimulating Hormone, Leutinizing Hormone,
Prolactin, Testosterone, Estrogen and β-HCG) in
Laboratory Rabbits
H. B. Osadolor1* and J. A. Omo-Erhabor1
1
Department of Medical Laboratory Science, School of Basic Medical Sciences, University of Benin,
P.M.B.1154, Benin City, Nigeria.
Author’s Contributions
This work was carried out in collaboration between both authors. Author HBO designed the study,
wrote the protocol, draft of the manuscript and supervised the work from the beginning to completion
while author JAOE managed the literature searches, performed the study analysis and the statistical
analysis. Both authors read and approved the final manuscript.
Article Information
DOI: 10.9734/BJMMR/2016/24620
Editor(s):
(1) E. Umit Bagriacik, Department of Immunology, Gazi University, Turkey.
Reviewers:
(1) Amal I. Hassan, Nuclear Research Center, Egypt.
(2) Sateesh Kumar Vemula, Chaitanya College of Pharmacy Education and Research, AP, India.
(3) Paulo Renato de Oliveira, Universidade Estadual do Centro Oeste, Brazil.
Complete Peer review History: http://sciencedomain.org/review-history/13836
Original Research Article
Received 27th January 2016
th
Accepted 12 March 2016
Published 24th March 2016
ABSTRACT
Drug abuse in Nigeria has been indicated to be on the rise in recent years. The use of hard drugs
and misuse of prescription drugs for nonmedical purposes cuts across all strata, especially the
youths. Tramadol (2[(Dimethylamin) methyl]-1-(3-methoxyphenyl)cyclohexanol) is known for its
analgesic potentials. This potent opioid pain killer is misused by Nigerian youths, owing to its
suspicion as sexual performance drug. This study therefore is aimed at determining the effect of
tramadol on hormone levels its improved libido properties and possibly fertility. Twenty seven (27)
European rabbits weighing 1.0 to 2.0 kg were used. Animals were divided into four major groups
consisting of male and female control, and male and female tramadol treated groups. Treated
groups were further divided into oral and intramuscular (IM) administered groups. Oral groups were
administered 25 mg/kg b.w. of tramadol per day while the IM groups received 15 mg/kg b.w. per
_____________________________________________________________________________________________________
*Corresponding author: E-mail: [email protected];
Osadolor and Omo-Erhabor; BJMMR, 14(8): 1-11, 2016; Article no.BJMMR.24620
day over a period of thirty days. Blood samples were collected at the end of the experiment for
progesterone, testosterone, estrogen (E2), luteinizing hormone, follicle stimulating hormone (FSH),
β-human chorionic gonadotropin and prolactin estimation. Tramadol treated groups were
compared with control groups at the end of the study, as well as within group comparison was
done. From the results, FSH was found to be significantly reduced (p<0.05) while LH increased
significantly (p<0.05). A decrease was observed for testosterone (p<0.001), and estrogen, FSH,
progesterone also decreased (p<0.05). Significant changes weren’t observed when IM groups
were compared with oral groups. This study does not support an improvement of libido by
tramadol, though its possible usefulness in the treatment of premature ejaculation may have been
established, but its capabilities to induce male and female infertility is still in doubt.
Keywords: Benin City; Nigeria; animal model; drug abuse.
Tramadol is frequently been abused in Northern
Nigeria by youths for lasting energy [7] and
sexual performance drug [8]. The use of this
potent opioid pain medication as sexual
enhancer and proposed management of
premature ejaculation as proposed by [9-13] as
well as the effectiveness of tramadol in the
treatment of premature ejaculation as show by
[14] have given rise to this study. This study aims
at evaluating the toxic effects of tramadol on sex
hormone profile of male and female Oryctolagus
cuniculus (European rabbits) with a view to
ascertaining if any its effects on libido and
possibly fertility.
1. INTRODUCTION
Drug abuse is the recurrent use of illegal drugs,
misuse of prescription and/or over the counter
drugs with negative consequences. Drug abuse
in Nigeria has been indicated to be on the rise in
recent years. NDLEA pointed that Kano State
has the highest drug abuse rates based on the
number of seizures, arrests of addicts and
convictions of arrested dealers [1]. This use of
hard drugs as well as misuse of prescription
drugs for nonmedical purposes cut across all
strata especially the youths. Among the drugs
being used are alcohol, caffeine, cannabis,
opiates and prescription and over the counter
drugs. Such abused drugs include alcohol,
tobacco, heroin, opiates e.t.c. [2]. Youths are
known to continue using these drugs despite the
major risk behaviours with its accompanied
physical and mental health complications [3].
Of growing interest is the increased demand
for
tramadol
which
is
an
opiate
analgesic medication. 2[(Dimethylamin)methyl]1-(3-methoxyphenyl)cyclohexanol also known as
tramadol is a common over the counter drug sold
in pharmaceutical shops and retail medicine
outlets in Nigeria. It is an opioid pain medication
for the treatment of moderate to moderately
severe pain. Available dosage forms include
capsules, tablets and extended release
formulations and injections [4].
2. MATERIALS AND METHODS
2.1 Dosing and Experimental Animals
Twenty seven (27) European rabbits aged
between 4-6 months, weighing 1.0 to 2.0 kg
purchased from local market in Benin City were
used for this study. The drug tramadol HCl
(Ampoule) 100 mg/2 ml manufactured by Gland
Pharma Limited, India was administered
intramuscularly while Nkoyo tramadol (Tramadol
capsule B.P. 100 mg) manufactured by Mancare
Pharma Pvt. Ltd. Vasai, India was administered
orally. Rabbits were left in the animal’s house for
two week before experimentation to adapt and
acclimatize to laboratory conditions of natural
light and dark cycle and given free access to
commercial balanced diet and tap water ad
libitum all through the experimental period.
Animals were divided into four groups consisting
male and female controls, and male and female
tramadol treated groups. Tramadol treated
groups were further divided into oral and
intramuscular (IM) groups. IM groups were
inoculated with 15 mg/kg b.w./day for thirty days
while orally groups were administered 25 mg/kg
b.w./day for thirty days.
Tramadol has been shown to have high
bioavailability with a range of 70-80% with peak
blood levels of about 2 hours following
oral administration. It is metabolized in the
liver by cytochrome P450 [5]. Bio-transformed
to five different metabolites of which Odesmethyl-tramadol is the most significant and is
2-4 times more active than tramadol [6]. Byproducts of tramadol are excreted through the
kidneys [5].
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Osadolor and Omo-Erhabor; BJMMR, 14(8): 1-11, 2016; Article no.BJMMR.24620
2.2 Measurement of Hormone Levels
2.4 Ethics
Blood samples were collected from tramadol
treated groups and control groups at the end of
the experiment into plain sample bottles and
serum transferred into a second plain bottle after
allowing to clot. Samples were stored at -70°C
until ready for assay. Human prolactin, folliclestimulating hormone, luteinizing hormone,
testosterone, progesterone, estradiol (E2) and
human chorionic gonadotropin (HCG) were
determined using i-chroma immunoassay
analysis system [15].
This study was approved by Ministry of Health,
Benin City, Edo State of Nigeria.
2.3 Statistics
Effect of tramadol on FSH, LH, Prolactin,
Testosterone, Estrogen and β-HCG was
estimated. All β-HCG levels were <5.0 mmol/L.
Fig. 1, shows the assessment of LH and FSH in
serum.
When
tramadol
treated
groups
were compared with control groups, FSH was
found to be significantly reduced (p<0.05)
while LH increased significantly (p<0.05). But on
comparison of male and female treated
groups with control groups (Fig. 3), and Oral and
IM groups with control groups as well as
among
themselves
(Fig.
2),
p-values
showed no significance both for LH and FSH
(p>0.05).
2.5 Informed Consent
It was not possible to get informed consent from
the rabbits, however all the rabbits were given
adequate care and treatment as if they were
human beings.
3. RESULTS
GraphPad Prism (version 6.04; GraphPad
Software, USA) was used for statistical analysis.
Error bars were reported as means ± SEM.
Statistical significance was determined using
Student t-Test, and one-way ANOVA to compare
tramadol treated groups and controls groups as
well as tramadol Oral administered groups with
Intramuscular administered groups and with
controls; and Two-way ANOVA to compare male
and female tramadol treated groups with male
and female control groups respectively.
Statistically significant levels of p<0.05 was used.
Fig. 1. LH and FSH estimation of control groups and tramadol treated groups
Error bars represent Mean ± SEM (*p<0.05)
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Osadolor and Omo-Erhabor; BJMMR, 14(8): 1-11, 2016; Article no.BJMMR.24620
Fig. 2. LH and FSH estimation of control groups, oral and IM tramadol treated groups
Error bars represent Mean ± SEM
Fig. 3. LH and FSH estimation showing male and female comparison
Error bars represent Mean ± SEM
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Osadolor and Omo-Erhabor; BJMMR, 14(8): 1-11, 2016; Article no.BJMMR.24620
Increased Prolactin level was observed
when tramadol treated groups were compared
with control groups (Fig. 4) although this
increase
wasn’t
significant
(p>0.05).
Testosterone levels on the other hand
showed significant decrease on comparison of
tramadol treated groups with control groups
(p<0.01). Within group (male and female treated
groups against male and female control
groups) comparison, and oral against IM and
control
groups
comparisons
show
no
significant
difference
for
prolactin
and
testosterone (p>0.05) (Fig. 6 and Fig. 5
respectively).
Fig. 4. Prolactin and testosterone estimation of control groups and tramadol treated groups
Error bars represent Mean ± SEM. (**p<0.01)
Fig. 5. Prolactin and testosterone estimation of control groups, oral and IM tramadol treated
groups
Error bars represent Mean ± SEM
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Osadolor and Omo-Erhabor; BJMMR, 14(8): 1-11, 2016; Article no.BJMMR.24620
On Estradiol estimation, a significant decrease
was observed (p<0.05) (Fig. 7). When Oral and
IM groups were compared with Control groups
(Fig. 8) and on comparison of male and female
treated groups with control groups (Fig. 9), no
significance was observed (p>0.05).
These effects include decreased levels of sex
hormones including testosterone and estrogen.
Cortisol and dehydropiandrosterone sulfate
(DHEAS) decreases have also been reported
[16].
A
significant
decrease
in
testosterone,
progesterone and estrogen levels were
seen in this study which correlates with [16]
suggesting that long term opioid therapy
results in clinically relevant suppression of
both hypothalamopituitary-adrenal and –gonadal
axes with
suppression
in
testosterone,
estrogen and cortisol. This effect as seen in this
sub-acute study may be attributed to suppression
of the hypothalamic-pituitary-gonadal axis
(HPG axis) by opioids [17,18]. Testosterone and
estrogen (the male and female principal
sex hormones) are produced by the testes
and ovaries respectively by the action of
FSH and LH (referred to as gonadotropins)
which
are
produced
by
the
pituitary
gland following the stimulation of gonadotropinreleasing
hormone
(GnRH)
which
in
turn is produced by the hypothalamus. It is
expected that as the level of sex hormones
rises a negative feedback loop should
trigger the hypothalamus to reduce production of
GnRH.
Determination of progesterone in tramadol
treated and control groups showed significant
decrease (p<0.05) (Fig. 10). When comparisons
were made between Oral and IM groups,
significance was observed between oral
administered groups and control groups (p<0.05)
although no significance was noticed between IM
and oral comparisons or IM and controls
(p>0.05) (Fig. 11). When comparisons were
made between groups of male and female
treated animals and control groups for male and
female animals, only male treated groups with
male control showed significance (p<0.05)
(Fig. 12).
4. DISCUSSION
Opioids are known to do well in relieve of pain.
This they do by turning on opioid receptors in the
brain, gastrointestinal tract and spinal cord. But
on long term usage, opioids have been reported
to have negative effects on hormone levels.
Fig. 6. Prolactin and testosterone estimation showing male and female comparison
Error bars represent Mean ± SEM
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Osadolor and Omo-Erhabor; BJMMR, 14(8): 1-11, 2016; Article no.BJMMR.24620
Fig. 7. Estradiol estimation of control groups and tramadol treated groups
Error bars represent Mean ± SEM
Fig. 8. Estradiol estimation of showing control groups, oral and IM tramadol treated groups
Error bars represent Mean ± SEM
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Osadolor and Omo-Erhabor; BJMMR, 14(8): 1-11, 2016; Article no.BJMMR.24620
Fig. 9. Estradiol estimation showing male and female comparison
Error bars represent Mean ± SEM
Fig. 10. Progesterone estimation of control groups and tramadol treated groups
Error bars represent Mean ± SEM
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Osadolor and Omo-Erhabor; BJMMR, 14(8): 1-11, 2016; Article no.BJMMR.24620
Fig. 11. Progesterone estimation of control groups, oral and IM tramadol treated groups
Error bars represent Mean ± SEM (*p<0.05)
Fig. 12. Progesterone estimation showing male and female comparison
Error bars represent Mean ± SEM
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Osadolor and Omo-Erhabor; BJMMR, 14(8): 1-11, 2016; Article no.BJMMR.24620
This study shows a reduction in sex hormones
without an adequate increase in gonadotropins
which should have been a proper hypothalamic
pituitary regulation. A reduction in sex hormones
by opioids have been reported previously by [17]
who demonstrated a reduction in testosterone
levels in the blood of Sprague-Dawley rats
following treatment with morphine; as well as in a
study of opioid induces endocrinopathy [18].
hypothalamus. Tramadol may also have direct
effect on the testes and ovaries causing reduced
testosterone and estrogen secretions. Also, long
term use could result in opiate induced
endocrinopathy which could predispose users to
cases of infertility for both male and females.
COMPETING INTERESTS
Authors have
interests exist.
Reduction in LH and FSH levels by opioids have
been reported previously by [18,19]. This study
showed a reduction in FSH levels which
correlates with previous studies indicating that
tramadol interferes with proper hypothalamic
pituitary regulation. This study showed an
increased LH levels which is in contrast to Todd
and colleague report of an inhibition of LH by
opioids. But in justification of [18], conclusion of
an incomplete understanding of the effect of
opioids on LH and subsequently sex hormone
release. Suggestions are that this interferences
experienced may be due to alterations in sex
hormone-hypothalamic feedback process.
declared
that
no
competing
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decrease in sexual drive as well as sustenance
of erection.
4.
5.
6.
Also, a malfunction in HPG axis can result in big
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7.
8.
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Although tramadol is being recommended in the
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no significant contributory effects on libido at the
concentration consumed through an alteration in
sex hormone patterns but that tramadol may
cause changes in sex hormone levels and alter
feedback regulations of the pituitary on the
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