1. health and fitness
2. disease
3. cholesterol

Sexual Function/Infertility
Efficacy of Coenzyme Q10 on Semen Parameters, Sperm
Function and Reproductive Hormones in Infertile Men
Mohammad Reza Safarinejad*
From the Urology and Nephrology Research Center, Shahid Beheshti University (MC), Tehran, Iran
Purpose: We determined the efficacy of coenzyme Q10 supplementation on semen parameters, sperm function and reproductive hormone profiles in infertile
men.
Materials and Methods: A total of 212 infertile men with idiopathic oligoasthenoteratospermia were randomly assigned to receive 300 mg coenzyme Q10
(Kaneka, Osaka, Japan) orally daily (106 in group 1) or a similar placebo regimen
(106 in group 2) during a 26-week period, followed by a 30-week treatment-free
phase. Two semen analyses, acrosome reaction test, immunobead test for antisperm antibody, and determination of resting levels of luteinizing hormone,
follicle-stimulating hormone, prolactin, testosterone and inhibin B were done in
all participants. Blood and seminal plasma total coenzyme Q10 was also assessed.
Results: Significant improvement in sperm density and motility was evident
with coenzyme Q10 therapy (each p ⫽ 0.01). Using the Kruger classification
sperm morphology evaluation revealed an increase in the percent of normal forms
in the coenzyme Q10 group (p ⫽ 0.07). A positive correlation was found between
treatment duration with coenzyme Q10 and sperm count (r ⫽ 0.46, p ⫽ 0.03) as
well as with sperm motility (r ⫽ 0.45, p ⫽ 0.04) and sperm morphology (r ⫽ 0.34,
p ⫽ 0.04). The coenzyme Q10 group had a significant decrease in serum folliclestimulating hormone and luteinizing hormone at the 26-week treatment phase
(each p ⫽ 0.03). By the end of the treatment phase the mean ⫾ SD acrosome
reaction had increased from 14% ⫾ 8% and 15% ⫾ 8% to 31% ⫾ 11% and 16% ⫾
10% in the coenzyme Q10 and placebo groups, respectively (p ⫽ 0.01).
Conclusions: Coenzyme Q10 supplementation resulted in a statistically significant improvement in certain semen parameters. However, further studies are
needed to draw a final conclusion and evaluate the effect of coenzyme Q10
supplementation on the pregnancy rate.
Abbreviations
and Acronyms
CoQ10 ⫽ coenzyme Q10
FSH ⫽ follicle-stimulating
hormone
LH ⫽ luteinizing hormone
PRL ⫽ prolactin
RCT ⫽ randomized, controlled
trial
TEAE ⫽ treatment emergent
adverse event
Submitted for publication November 5, 2008.
Study received approval from the Urology and
Nephrology Research Center human ethics committee.
* Correspondence: P. O. Box 19395-1849, Tehran, Iran (telephone: 0098 21 22454499; FAX:
0098 21 22456845; e-mail: [email protected]).
Key Words: testis; spermatozoa; infertility, male; coenzyme Q10;
dietary supplements
WORLDWIDE approximately 1 of 10 couples is infertile, which is due to male
factors in approximately half.1,2 Because the etiology and pathogenesis
are still not fully understood, a significant proportion of male infertility is
considered idiopathic and is usually
accompanied by oligoasthenoterato-
spermia. Recently worldwide concerns
have been raised about the impact of
industrialization on public health. Indeed, during the last decades there
has been evidence of decreasing sperm
quality because of the use of chemicals and repeat exposure to hazardous
compounds at work.3 The distress and
0022-5347/09/1821-0237/0
THE JOURNAL OF UROLOGY®
Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 182, 237-248, July 2009
Printed in U.S.A.
DOI:10.1016/j.juro.2009.02.121
www.jurology.com
237
238
COENZYME Q10 AND SEMEN PARAMETERS
personal devastation experienced by couples with
infertility has been documented since the beginning
of recorded time in cultures throughout the world.
The social and psychological consequences of involuntary childlessness in developing countries are
more severe. Common scenarios include unstable
marriages, divorce, polygamy and ostracism of the
women.4
Modern medicine has made several advances in
the diagnosis, treatment and prevention of infertility. However, most infertile men with idiopathic oligoasthenoteratospermia have remained untreated.
Treatment for idiopathic male infertility is empirical. For whatever reason the possible role of these
treatments on idiopathic oligoasthenoteratospermia
has failed to gain wider acceptance.
It is known that excess reactive oxygen species
impairs sperm cell function and has a negative role
in male fertility. CoQ10 or ubiquinone, an isoprenylated benzoquinone that transports electrons from
complexes I and II to complex III in the mitochondrial respiratory chain, is essential for the stability
of complex III.5 In addition, CoQ10 is an antioxidant, an energy promoting agent, a membrane stabilizer and a regulator of mitochondrial permeability transition pores.6 In sperm cells most CoQ10 is
concentrated in the mitochondria of the mid piece
and energy dependent processes in the sperm cell
depend on the availability of CoQ10.7 CoQ10 in seminal fluid shows a direct correlation with semen parameters.8 CoQ10 has 2 forms, that is reduced
(ubiquinol) and oxidized (ubiquinone) forms. A
strong correlation among sperm count, motility and
ubiquinol-10 content in seminal fluid has been reported.9 In a recent study exogenous administration
of CoQ10 was effective for improving sperm kinetic
features in patients with idiopathic asthenozoospermia.10
To our knowledge, while a previous RCT exists of
the role of CoQ10 supplementation in semen parameters, this is the first study to look at sperm function
and the hormone profile in infertile men with idiopathic oligoasthenoteratospermia.
Diagnosis of a fertile female partner was based on history,
physical examination, baseline body temperature, luteal
phase progesterone, normal hematological and biochemical investigations, normal sexual hormones, absent sperm
immobilizing antibodies in serum and a normal hysterosalpingogram. Cervical cultures for Ureaplasma, Mycoplasma, Chlamydia and bacterial vaginosis were also done
as needed. Female partners with abnormal findings on
hysterosalpingography underwent laparoscopy.
Trial requirements were explained to participants. We
explained that determining the effect of any intervention
to treat male factor infertility requires at least a 6-month
period, that is 2 spermatogenesis cycles.
Study Inclusion Criteria
Patients were included in the study after fulfilling certain
criteria, including unwilling childlessness at least 24
months in duration with a female partner, no known medical condition that could account for infertility, total testicular volume 12 ml or greater on ultrasound and a normal fertile female partner according to investigations. All
patients were required to have ceased all medical therapy
at least 12 weeks before study initiation. Only patients
seeking medical attention for the disease were included in
this study.
Study Exclusion Criteria
Exclusion criteria were azoospermia or severe oligospermia (sperm count less than 5 million per ml); a history of
epididymo-orchitis, prostatitis, genital trauma, testicular
torsion, inguinal or genital surgery, urinary tract infection
or previous hormonal therapy; another genital disease
(cryptorchidism, current genital inflammation or varicocele); severe general or central nervous system disease
and endocrinopathy; use of cytotoxic drugs, immunosuppressants, anticonvulsives, androgens or antiandrogens;
and a recent history of sexually transmitted disease. Patients were also excluded from analysis if they had psychological or physiological abnormalities that would impair sexual performance or the ability to provide semen
samples; drug, alcohol or substance abuse; hepatobiliary
disease; significant renal insufficiency; Y chromosome microdeletions or karyotype abnormalities; occupational and
environmental exposures to potential reproductive toxins;
a body mass index of 30 kg/m2 or greater; participation in
another investigational study; and unlikely availability
for followup.
Evaluations
MATERIALS AND METHODS
A total of 268 infertile males between 21 and 42 years old
with idiopathic oligoasthenoteratospermia were enrolled
in the study from February 2005 to October 2006. All men
presenting for infertility treatment had had a minimum of
2 years of unprotected intercourse. Male infertility was
diagnosed if 1 or more standard semen parameters were
below the cutoff levels accepted by WHO (sperm density
less than 20 ⫻ 106/ml, sperm motility less than 50%,
normal morphology less than 30% and/or semen volume
less than 2 ml) based on at least 2 semen analyses performed 3 months apart to eliminate accidental and possible adverse effects of various factors on spermatogenesis.
After providing a complete medical and reproductive history exploring all aspects that may be related to fertility
patients underwent physical examination, urinalysis, and
serum chemical and hematological laboratory tests. All
patients were asked to complete a face-to-face questionnaire, including occupational history and lifestyle. The
presence of varicocele was determined by Doppler ultrasonography of the scrotum with the Valsalva maneuver.
Testicular volume was measured using the formula of
Behre et al11 with a volume of less than 12 ml considered
small. Serum hormonal evaluation, including FSH, LH,
inhibin B, PRL and testosterone, were performed in each
patient. Additional safety evaluations, including measurement of serum aspartate aminotransferase, alanine ami-
COENZYME Q10 AND SEMEN PARAMETERS
notransferase, lactic dehydrogenase, creatine kinase, alkaline phosphatase and glucose, were also determined at
baseline and at each followup point. Genetic testing included karyotype analysis and Y chromosome microdeletion analysis in patients with a sperm count of less than
10 ⫻ 106/ml. Also, blood and seminal plasma specimens in
each participant were analyzed for the CoQ10 concentration.
All patients underwent at least 2 baseline semen analyses. When values differed by more than 20%, a third test
was done. All semen samples were obtained in a sterile
wide mouth and metal-free plastic container after 3 days
of recommended sexual abstinence. In addition, every participant completed a form about sperm collection information. Samples were delivered to the fertility laboratory
within 1 hour after production. All procedures and interpretations used were in accordance with established 1992
WHO criteria. Morphology was established according to
the Kruger parameters.
Normal values were considered to be volume 2.0 ml or
greater, sperm density 20 ⫻ 106/ml or greater and motility
50% or greater with forward progression. Semen volume
was measured in a 15 ml conical tube. Sperm density and
percent motility were assessed in a Makler counting
chamber using the Hamilton-Thorn automated system
(Hamilton-Thorn Research, Beverly, Massachusetts). Percent motile sperm was calculated using WHO criteria,
including grade A sperm—rapidly progressive with a velocity of 25 ␮m per second or greater at 37C and B grade
sperm—slow/sluggish progressive with a velocity of 5 ␮m
per second or greater but less than 25 ␮m per second.12
Using the Kruger strict criteria males with greater than
14% normal forms were considered normal.
A total of 100 consecutive sperm were scored in each of
2 selected areas of a single slide. For strict morphology
when the absolute percent of normal sperm from the 2
areas of the slide differed by more than 5%, an additional
100 sperm were scored from a third area. Samples were
assessed at least twice for volume, sperm density, progressive and total motility, and the percent normal forms. All
semen analyses were performed by the author (MRS) and
the same laboratory technicians.
The total motile sperm count was determined by the
formula, (semen volume ⫻ sperm density ⫻ motility percent)/100. Strict quality control measures were enforced
throughout the entire study. Quality control and proficiency criteria were set for less than 15% variation to
certify the technician trained to do semen analysis in the
study. In every patient the immunobead test for antisperm antibody binding was also performed. As a sperm
function test, the acrosome reaction assay was done.
239
sured using immunochemiluminometric assay with an intra-assay and interassay coefficient of variation of 3.2%
and 6.7%, respectively. The normal FSH range is 1.4 to
18.1 IU/l. Serum inhibin B was determined by enzymelinked immunosorbent assay using kit reagents and inhibin B standard (Oxford Bio-Innovation, Oxon, United
Kingdom). Assay sensitivity was 4 pg/ml and between
assay variation was 15%.
Blood and seminal plasma samples were analyzed for
total CoQ10 using high performance liquid chromatography with an electrochemical detector using methodology
adapted from that of Tang et al.13 Between and within run
coefficients of variation for total CoQ10 measurement
were approximately 3.3%. The normal reference range for
the total concentration of the reduced and oxidized forms
of CoQ10 in the blood plasma of healthy individuals is 0.4
to 2.0 ␮g/ml.
There was strict quality control. Precision of the
method was measured by coefficients of variation. The
mean coefficient of variation for CoQ10 measurement in
blood and seminal plasma was 2.1% for within day determinations and 2.8% for day-to-day determinations.
Antibodies bound to the surface of sperm were detected
with the immunobead binding test. Antisperm antibody
assay was performed using specific beads that bind separately to IgG and IgA. Antisperm antibody assay was
considered positive when there were more than 20%
sperm bound immunobeads, according to 1992 WHO recommendations.14
Acrosome Reaction Assay
Sperm from 1 sample was incubated at 37C in a 5%
CO2/air environment for 6 hours with a 5 mmol/l solution
of calcium ionophore A 23187. Samples were then fixed in
Carnoy’s fixative and stained using the triple stain technique of Garde et al.15 Subsequently we determined the
percent of sperm showing vesiculation and membrane disruption in the acrosomal region. The test was considered
positive when the acrosomal reaction occurred in 30% or
more of the sperm and negative when it occurred in less
than 30%.16
All patients who met study inclusion and exclusion
criteria provided informed consent before entering the
study, which was done in accordance with International
Conference on Harmonisation-Good Clinical Practice
guidelines and the principles of the Declaration of Helsinki. The human ethics committee at the Urology and
Nephrology Research Center approved the study protocol.
No remuneration was offered. Of the 268 screened patients 212 met inclusion/exclusion criteria and consented
to proceed with the study protocol.
Laboratory Methods
Study Design
Serum testosterone and PRL were assayed using commercial radioimmunoassay kits. These commercial kits had
been previously used with an interassay and intra-assay
variation of less than 10%. The reference range for testosterone and PRL is 10 to 35 nmol/l and 92 to 697 pmol/l,
respectively. LH was measured by immunochemiluminometric assay, in which intra-assay and interassay coefficients of variation were 3.4% and 3.8%, respectively. The
normal LH range is 1.5 to 9.3 IU/l. FSH was also mea-
The study consisted of a 4-week screening phase, a 26week treatment phase and a 30-week treatment-free period (fig. 1). At the beginning of the study qualifying patients were randomized to treatment with CoQ10 or
placebo. Each eligible patient received a randomization
number, which was determined by a computer generated
schedule. Thereafter a randomization table was generated
by the method of random permuted blocks. Individuals
who were geographically and operationally independent of
240
COENZYME Q10 AND SEMEN PARAMETERS
Figure 1. Study design
the study investigator performed the study randomization. The clinician prescriber and patients were blinded to
the treatment condition. To maintain and guarantee
blinding CoQ10 and placebo were identical in appearance.
Participant data collected during this trial were kept confidential and locked in a secure office area. Randomization
codes were opened only after all patients had completed
the whole study protocol.
Patients were randomized to group 1—106 who received 300 mg CoQ10 once daily and group 2—106 who
received matching placebo for 26 weeks. The existing literature suggests that 200 mg CoQ10 daily for 12 weeks
are sufficient to restore the plasma CoQ10 concentration.17 Compliance was assessed by comparing the number of pills ingested with the number of days between
dispensing visits. Followup points were weeks 4, 8, 12, 16,
20, 26, 32, 40, 46, 52 and 56. At each followup visit 2
semen samples were collected within a 1 to 2-week period.
Measurement of blood and seminal plasma CoQ10, determination of serum testosterone, prolactin, inhibin B, LH
and FSH, and additional safety evaluations were done at
each followup visit. The study protocol also included
monthly contact to deliver study medications and evaluate
compliance and TEAEs.
Safety and Tolerability Assessment
Safety and tolerability were evaluated based on spontaneously reported adverse effects and physical examination
during each patient visit. TEAEs were defined as unfavorable medical events, such as subjective symptoms, objective symptoms or unfavorable abnormal clinical data, that
the volunteers commented on after receiving the prescribed material regardless of whether they appeared to
be related to the test material. The Medical Dictionary for
Regulatory Activities, version 5.0 was used to determine
severity and the relationship to study drug assessed
TEAEs. When there was an adverse event, the patient
was treated as required.
Statistical Analysis
The investigator was responsible for accurate and complete data collection. Data are presented as the mean ⫾
SD unless otherwise stated. Analysis was performed according to per protocol analysis. The primary efficacy end
point was the change in semen parameters from baseline
to week 26. The null hypothesis was that CoQ10 and
placebo did not differ on all primary efficacy variables. To
reject the null hypothesis a 2-tailed significance of 0.05
was required. A sample size of 200 patients, that is 100
per group, was calculated to provide greater than 90%
power to detect a significant treatment effect in each primary efficacy variable at ␣ ⫽ 0.05. ANCOVA was used to
evaluate the primary efficacy end points. In addition, the
change from baseline in efficacy measures was assessed
using ANCOVA models with terms for the baseline value
of the efficacy variable and the treatment group. All patients who received at least 1 dose of study medication and
who had posttreatment data available were evaluated for
safety.
The unpaired t test was used to compare laboratory
variables between the CoQ10 and placebo groups. Correlations were assessed by Spearman’s rank correlation test
with p ⬍0.05 considered statistically significant. Statistical analysis was performed using SPSS® Base, version
10.0 and SigmaStat®.
RESULTS
Patient Characterization
Table 1 lists baseline characteristics of the study
patients. Those who received CoQ10 supplement
and those who received placebo were similar in baseline characteristics. Compliance was greater than
90% in all patients. A total of 212 patients were
recruited but only 194 (91.5%) completed the whole
study, including 98 of 106 in the CoQ10 group and
96 of 106 in the placebo group (fig. 2). A total of 18
patients (8.5%) did not complete the study because
of withdrawal of consent in 5 (2 in the CoQ10 group
and 3 in the placebo group), loss to followup in 6 (3
per group) and missing data in 7 (3 in the CoQ10
group and 4 in the placebo group). The dropout rate
was not significantly different between the 2 groups
(p ⫽ 0.08).
COENZYME Q10 AND SEMEN PARAMETERS
Table 1. Baseline patient demographics, serum hormones and
semen parameters
Characteristics
Age
Body mass index (kg/m2)
Serum hormones:
Testosterone (nmol/l)
LH (IU/l)
FSH (IU/l)
PRL (pmol/l)
Inhibin B (ng/l)
Plasma CoQ10:
Blood (␮g/ml)
Semen (ng/ml)
% Acrosome reaction
% Immunobead binding test:
IgG
IgA
Semen parameters:
Ejaculate vol (ml)
Total sperm/ejaculate (⫻106)
Sperm density (⫻106/ml)
% Motility
% Normal strict morphology
Mean ⫾ SD
CoQ10*
28 ⫾
26.6 ⫾
15.8
12.1
16.7
374
86
9
2.7
⫾ 5.4
⫾ 2.6
⫾ 4.1
⫾ 120
⫾ 24
1.1 ⫾ 0.6
37.6 ⫾ 10.2
34 ⫾ 8
4.12 ⫾ 10.62
3.27 ⫾ 8.32
2.7
46.6
20.2
22.2
7.2
⫾ 1.3
⫾ 12.6
⫾ 4.6
⫾ 2.4
⫾ 2.6
Mean ⫾ SD
Placebo*
28 ⫾ 10
26.4 ⫾ 2.4
15.6
12.4
16.6
361
87
⫾ 4.8
⫾ 2.4
⫾ 4.1
⫾ 123
⫾ 26
1.1 ⫾ 0.4
38.2 ⫾ 11.6
35 ⫾ 8
4.14 ⫾ 11.12
3.29 ⫾ 8.32
2.8
47.2
20.4
22.3
7.3
⫾ 1.4
⫾ 12.2
⫾ 4.4
⫾ 2.6
⫾ 2.7
* Total of 106 patients per group (each p not significant).
Testicular Volume and Semen Parameters
At the end of week 56 testicular volume in the
CoQ10 group did not differ significantly from that in
the placebo group (23.6 ⫾ 2.8 and 22.9 ⫾ 2.8 ml,
respectively, p ⫽ 0.07). Table 2 shows posttreatment
and 56-week followup period semen parameters.
241
The most improved posttreatment semen analysis was used for data analysis. Statistically significant differences were found between the groups in
26-week sperm count and motility values (p ⫽ 0.01).
However, a significant difference was not found in
sperm morphology (p ⫽ 0.07). At the end of 56-week
treatment-free phase all 3 semen parameters (count,
motility and morphology) in the CoQ10 group were
higher than those in the placebo group but this did
not attain statistical significance (each p ⫽ 0.07).
The mean percent change in semen parameters from
baseline at the 8, 16 and 26-week treatment phases
were different from each other in the CoQ10 group
(fig. 3). A positive correlation was found between
treatment duration with CoQ10 and sperm count
(r ⫽ 0.46, p ⫽ 0.03) as well as mean sperm motility
(r ⫽ 0.45, p ⫽ 0.04) and sperm morphology (r ⫽ 0.34,
p ⫽ 0.04). At the 26-week treatment phase the increment from baseline in sperm density was 21.5%
in the CoQ10 group and 1.3% in the placebo group
(p ⫽ 0.01, table 3). The percent change from baseline
in sperm motility was 30.7% and 2% in the CoQ10
and placebo groups, respectively (p ⫽ 0.01). Participants treated with CoQ10 and placebo had a 33.3%
and 6.8% increase in strict morphology, respectively
(p ⫽ 0.01). Figure 4 shows the percent change from
baseline in semen parameters at various study
points.
By the end of the treatment phase the percent of
acrosome reaction had increased from 34 ⫾ 8 and
35 ⫾ 8 to 41 ⫾ 11 and 36 ⫾ 10 in the CoQ10 and
Figure 2. Participant flow diagram
242
COENZYME Q10 AND SEMEN PARAMETERS
Table 2. Semen parameters, reproductive hormones and CoQ10 at various assessment points
26 Wks*
Mean ⫾ SD
CoQ10
Parameters
Total sperm count (⫻106)
Sperm density (⫻106/ml)
Ejaculate vol (ml)
% Sperm motility
% Normal strict morphology
Serum hormones:
Testosterone (nmol/l)
LH (IU/l)
FSH (IU/l)
PRL (pmol/l)
Inhibin B (ng/l)
Plasma CoQ10:
Blood (␮g/ml)
Seminal (ng/ml)
% Acrosome reaction
% Immunobead binding
test:
IgG
IgA
p Value
vs
Baseline
56 Wks*
Mean ⫾ SD
Placebo
p Value
vs
Baseline
Mean ⫾ SD
CoQ10
p Value
vs 26
Wks
Mean ⫾ SD
Placebo
p Value vs
26 Wks/CoQ10
56 Wks
57.6
26.4
2.7
27.6
9.6
⫾ 14.4
⫾ 4.4
⫾ 1.4
⫾ 2.2
⫾ 2.4
0.01
0.01
0.1
0.01
0.07
47.8
20.8
2.7
23.1
7.8
⫾ 11.2
⫾ 4.3
⫾ 1.7
⫾ 2.1
⫾ 2.1
0.1
0.1
0.1
0.08
0.1
51.7
22.8
2.7
24.2
8.2
⫾ 12.4
⫾ 3.8
⫾ 1.3
⫾ 2.1
⫾ 2.1
0.07
0.07
0.1
0.07
0.08
47.8
21.2
2.8
22.8
7.4
⫾ 11.6
⫾ 3.8
⫾ 1.2
⫾ 2.2
⫾ 1.8
0.1/0.07
0.1/0.08
0.1/0.1
0.1/0.07
0.1/0.07
18.6
8.8
10.7
368
105
⫾ 5.6
⫾ 2.6
⫾ 4.1
⫾ 118
⫾ 28
0.07
0.03
0.03
0.1
0.03
15.8
12.6
16.8
365
88
⫾ 4.6
⫾ 2.4
⫾ 4.2
⫾ 121
⫾ 25
0.1
0.1
0.1
0.1
0.1
16.4
10.1
14.4
376
94
⫾ 5.1
⫾ 2.3
⫾ 3.8
⫾ 120
⫾ 22
0.08
0.08
0.08
0.1
0.08
15.7
12.4
16.6
362
87
⫾ 4.4
⫾ 2.2
⫾ 4.4
⫾ 118
⫾ 20
0.1/0.08
0.1/0.08
0.1/0.08
0.1/0.08
0.1/0.08
2.04 ⫾ 0.8
88.4 ⫾ 12.6
41 ⫾ 11
0.01
0.01
0.01
1.1 ⫾ 0.5
38.4 ⫾ 11.2
36 ⫾ 10
0.1
0.1
0.1
1.1 ⫾ 0.4
37.8 ⫾ 11.2
38 ⫾ 11
0.01
0.01
0.01
1.1 ⫾ 0.4
37.9 ⫾ 11.6
35 ⫾ 12
0.1/0.1
0.1/0.1
0.1/0.08
4.18 ⫾ 10.58
3.24 ⫾ 8.72
0.1
0.1
4.13 ⫾ 12.1
3.44 ⫾ 8.76
0.1
0.001
4.14 ⫾ 11.12
3.41 ⫾ 9.12
0.1
0.1
4.11 ⫾ 10.44
3.48 ⫾ 8.76
0.1/0.1
0.1/0.1
* Total of 106 patients per group.
placebo groups, respectively (p ⫽ 0.01). The acrosome reaction had a significant positive correlation
with sperm density (r ⫽ 0.48, p ⫽ 0.03), mean sperm
motility (r ⫽ 0.49, p ⫽ 0.03) and sperm morphology
(r ⫽ 0.42, p ⫽ 0.03, table 3).
Serum Hormones
Mean serum LH, FSH, PRL, inhibin B and testosterone were not significantly different between the
groups at baseline (each p ⫽ 0.1, table 1). When
comparing the CoQ10 supplemented group with the
placebo group, the CoQ10 group had a significant
decrease in serum FSH and LH at the 26-week
treatment phase (each p ⫽ 0.03, table 2). At the end
of the 56-week treatment-free phase serum FSH and
LH in the CoQ10 group were lower than those in the
placebo group but the difference was not statistically
significant (p ⫽ 0.08). At baseline mean serum inhibin B was at the lower limit of normal reference
range. By the end of the 26-week treatment period
serum inhibin B had significantly increased in the
CoQ10 group compared with that in the placebo
group (p ⫽ 0.03, table 2). A positive correlation existed between serum inhibin B and sperm density
(r ⫽ 0.42, p ⫽ 0.02). The mean change from baseline
in serum LH, FSH, testosterone and inhibin B was
different in the group treated with CoQ10 at 4, 8, 12,
16 and 26 weeks of treatment (fig. 5). Changes in
serum testosterone and inhibin B were 17.7% and
22.1% in the CoQ10 group, and 1.3% and 1.1% in the
placebo group (p ⫽ 0.02 and 0.01, respectively). The
most striking changes in serum hormones occurred
in FSH. Serum FSH decreased by 35.9% in the
CoQ10 group and it increased by 1.2% in the placebo
group (p ⫽ 0.01, table 3). Table 3 and figure 6 show
detailed explanations about changes from baseline
in serum hormones. Semen volume and binding of
antisperm antibody of the IgG and IgA types were
not influenced by either treatment (table 2).
Blood and Semen CoQ10
Oral supplementation with 300 mg CoQ10 daily increased blood and seminal plasma CoQ10. At the
end of the 26-week treatment period the percent
increase in blood plasma and seminal plasma CoQ10
was 85.5% and 135.1% in the CoQ10 group, and 0%
and 0.5% in the placebo group, respectively (each
p ⫽ 0.001, table 3). Changes in blood plasma CoQ10
showed significant positive correlations with the
changes in seminal plasma CoQ10 (r ⫽ 0.62, p ⫽ 0.02).
Total blood plasma CoQ10 reached a maximum in 2
weeks, after which it remained stable for 4 weeks.
By 2 weeks after withdrawal plasma CoQ10 had
decreased to the baseline level. The pattern of the
change in seminal plasma CoQ10 was somewhat
different than the pattern observed in blood plasma.
Seminal plasma CoQ10 reached a plateau by week
8. By the end of followup at week 56 the blood and
seminal plasma CoQ10 concentrations were not significantly different from baseline. There were strong
and significant correlations between seminal plasma
CoQ10 and sperm count (r ⫽ 0.77, p ⫽ 0.01), sperm
motility (r ⫽ 0.76, p ⫽ 0.01) and sperm morphology
(r ⫽ 0.54, p ⫽ 0.02).
COENZYME Q10 AND SEMEN PARAMETERS
243
Figure 3. Mean sperm density, total sperm count, sperm with normal morphology and sperm motility during treatment and followup.
Single asterisk indicates number of patients analyzed in CoQ10 group. Double asterisks indicate number of patients analyzed in placebo
group.
Safety and Adverse Events
No side effects were observed due to the oral administration of CoQ10 in any participants. CoQ10 re-
sulted in no clinically significant changes in vital
signs, urinalyses, serum chemical values or hematological values. There were no serious adverse
Table 3. Change in measured variables from baseline during study period
26-Wk Treatment
Parameters
Total sperm count
Sperm density
Ejaculate vol
Sperm motility
Strict morphology
Serum hormones:
Testosterone
LH
FSH
PRL
Inhibin B
Plasma CoQ10:
Blood
Seminal
Acrosome reaction
Immunobead binding test:
IgG
IgA
% CoQ10
56-Wk Recovery
% Placebo
p Value
% CoQ10
% Placebo
p Value
21.5
30.7
0
24.3
33.3
1.3
2
⫺3.6
3.6
6.8
0.01
0.01
0.08
0.01
0.01
10.9
12.9
0
9
13.9
1.3
2.9
0
2.2
1.4
0.03
0.03
—
0.04
0.03
17.7
⫺27.3
⫺35.9
⫺1.6
22.1
1.3
1.6
1.2
1.1
1.1
0.02
0.01
0.01
0.1
0.01
3.8
⫺16.5
⫺13.8
0.5
9.3
0.6
0
0
0.3
0
0.07
0.02
0.03
0.1
0.03
85.5
135.1
20.6
0
0.5
0.3
0.001
0.001
0.01
0
0.5
11.8
0
⫺0.8
0
—
0.1
0.03
1.5
⫺0.9
0.2
4.6
0.1
0.07
0.5
4.3
⫺0.7
5.8
0.1
0.1
244
COENZYME Q10 AND SEMEN PARAMETERS
Figure 4. Percent change from baseline in total sperm count, and sperm density, motility and morphology during whole study period
events and no study withdrawals due to adverse
events.
DISCUSSION
We examined the efficacy of CoQ10 for improving
semen parameters, sperm function and reproductive hormone profiles by performing a RCT. Controlled studies are mandatory for assessing any
clinical intervention for idiopathic oligoasthenoteratospermia. This study demonstrated that
daily administration of 300 mg CoQ10 for 26
weeks or approximately 2 human spermatogenesis
cycles significantly improved semen parameters
and sperm function testing, and altered reproductive hormones. However, the beneficial effects in
terms of semen parameters were modest. Mean
strict Kruger morphology values did not differ significantly from values in the placebo group (9.6 ⫾
2.4 and 9.6 ⫾ 2.4, respectively, p ⫽ 0.07). Although a statistically significant improvement in
density or motility was achieved in the CoQ10
group, there was no difference in the pregnancy
rate during the study period between the 2 groups.
The reasons for this apparent discrepancy lie in
the posttreatment semen parameters. Sperm motility was 27.6 ⫾ 2.2 per ml in the CoQ10 group
and 23.1 ⫾ 2.1 per ml in the placebo group, which
may not be clinically relevant. The 2 values are far
from the recommended normal value for sperm
motility (motility 50% or greater with forward progression). In addition, at the 26-week treatment
phase mean total sperm count in the CoQ10 group
was less than 60 million. However, semen analysis
is far from a perfect assessment of male reproductive potential and the fact that some infertile men
had semen analyses exceeding WHO criteria
COENZYME Q10 AND SEMEN PARAMETERS
245
Figure 5. Mean serum LH, FSH, testosterone and inhibin B during treatment and followup. Single asterisk indicates number of patients
analyzed in CoQ10 group. Double asterisks indicate number of patients analyzed in placebo group.
added to the difficulty. To our knowledge whether
a longer treatment trial or higher doses might
have resulted in better findings has yet to be identified.
There are a few noteworthy implications of our
study results. 1) CoQ10 supplementation may
have a potential clinical application in infertile
men. 2) Patients with idiopathic oligoasthenospermia may consume a diet that is inadequate in
CoQ10. 3) The usefulness of CoQ10 supplementation for achieving pregnancy in infertile couples
should be evaluated in further prospective studies. CoQ10 therapy was able to influence semen
parameters, probably by modifying the balance
between oxygen radicals and antioxidant defense.
To establish this point it is important to assess
oxidative stress and antioxidant levels in seminal
plasma at baseline and after therapy. We did not
do this, which is one of the study limitations.
Indexes of healthier seminiferous tubules are
higher inhibin B and lower FSH.18 Higher serum
FSH implies poorer spermatogenesis. Inhibin B
levels correlate with testis size and reflect Sertoli’s
cell function. There is negative feedback between
FSH and inhibin B. Improvement in seminiferous
tubules function is associated with improvement
in seminiferous tubules function indexes. After
CoQ10 supplementation serum FSH decreased by
35.9% and serum inhibin B increased by 22.1%
from baseline. These values were statistically significant compared with those in the placebo group.
This denotes that CoQ10 supplementation may
have a direct effect on the seminiferous tubule
level. In addition, we observed modest changes in
serum testosterone in the CoQ10 group. At the end
of 26 weeks of treatment with CoQ10 supplementation serum testosterone increased 17.7% from
baseline. However, mean ⫾ SD serum testosterone at the end of 26-week treatment phase did not
differ significantly from that in the placebo group.
In the current study sperm count and motility
were also improved after CoQ10 supplementation.
These results support the hypothesis that systemic CoQ10 supplementation causes more efficacious spermatogenesis by the seminiferous tubules, and the recovery of sperm count and
morphology.
The decrease in gonadotropins was associated
with improved spermatogenesis and increased serum inhibin B. The plasma CoQ10 concentration
is altered in pituitary diseases, such as acromegaly or secondary hypothyroidism.19 In addition,
246
COENZYME Q10 AND SEMEN PARAMETERS
Figure 6. Percent changes from baseline in serum testosterone, LH, FSH and inhibin B during whole study period
cholesterol and ubiquinone have a common biosynthetic pathway.19 Therefore, the role of CoQ10
in the pituitary-gonadal axis requires further clarification.
Mancini et al assayed the CoQ10 content in seminal plasma and seminal fluid in 77 patients with
normal or pathological findings on standard semen
analysis.20 They noted a significant correlation
among sperm count, motility and the CoQ10 content
in seminal fluid. Seminal plasma CoQ10 was low in
patients with asthenospermia. In addition, sperm
cells, which are characterized by low motility and
abnormal morphology, have low levels of CoQ10.21
Therefore, infertile men with idiopathic oligoasthenoteratospermia might benefit from CoQ10
supplementation. In a RCT Balercia et al evaluated the effectiveness of 200 mg CoQ10 per day for
improving semen quality in 60 men with idiopathic infertility.10 They found a weak linear relationship between seminal plasma or intracellu-
lar CoQ10 and semen kinetic parameters. The
study was flawed due to small sample size (30 men
per group). Moreover, many studies of semen analysis in men from various geographic regions have
revealed surprisingly different results at different
locations. This may be due to environmental factors, such as the type of food consumed and where
it is grown. These effects may adversely affect the
male endocrine and reproduction systems.
However, while published data are imperfect, they
suggest that certain medications may be beneficial to
male reproductive capacity, including trace elements.
In a double-blind, placebo controlled study 200 ␮g selenium orally daily for 26 weeks significantly improved all semen parameters.22 Recently Kumar et al
searched PubMed®/MEDLINE® using the key words
male infertility, treatment, therapy, oligospermia, asthenospermia, teratospermia androgens, testosterone,
gonadotropins, FSH, LH, GnRH, LH-RH, mesterolone,
clomifene, testolactone, tamoxifen, anastrozole, aro-
COENZYME Q10 AND SEMEN PARAMETERS
matase inhibitor, antiestrogens, antioxidant, lycopene,
␣ tocopherol, vitamin E, glutathione (L-␥-glutamyl-Lcysteinylglycine), carnitine, CoQ10 and coenzyme Q10
in various combinations.23 They concluded that drug
therapy for idiopathic male infertility is at best empirical. There is no clear benefit of using any medication
in these patients. Therefore, the approved and effective treatment for idiopathic oligoasthenoteratospermia has yet to be identified.
In the current study sperm density in patients
had a narrow range of 10 to 30 ⫻ 106/ml. The reason
is that 86.8% of the participants had oligospermia,
defined as sperm density less than 20 ⫻ 106/ml. In
addition, we excluded patients with azoospermia or
severe oligospermia, defined as a sperm count of less
than 5 million per ml. Sperm morphology was assessed using Kruger’s strict criteria. The Kruger
evaluation was done because of the possibility of
performing in vitro fertilization in any of these couples in the future after CoQ10 treatment. The association between sperm morphology as recorded by
strict criteria and the in vitro fertilization rates has
been well documented.24
Our study had the benefits of a placebo controlled,
randomized study design, patients with idiopathic
oligoasthenoteratospermia, sperm function test data
and serum reproductive hormone profile analysis. It
247
also had another important limitation. It is not clear
whether improved semen parameters translate directly to improved fertility. We did not address this
issue. None of the patients reported pregnancy during the study period. A more effective outcome parameter would probably be the pregnancy rate since
that is the ultimate end point of therapy.
The etiology of male factor infertility is frequently
multifactorial. Semen has a unique biochemical
composition and its biological function has never
been fully explained.
CONCLUSIONS
This study indicates that oral supplementation with
CoQ10 significantly improves semen parameters
compared with that of placebo. Although this observation may not be clinically relevant, we propose
that because of its antioxidant effects and safety
profile, CoQ10 should be considered a good candidate for treatment in infertile men with idiopathic
oligoasthenoteratospermia. A longer term study
with different treatment regimens is needed to draw
a final conclusion.
ACKNOWLEDGMENTS
Shiva Safarinejad assisted with the manuscript.
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