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Human semen quality in the new millennium: A prospective cross-sectional population-based study of 4867 men

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Considerable interest and controversy over a possible decline in semen quality during the 20th century raised concern that semen quality could have reached a critically low level where it might affect human reproduction. The authors therefore initiated a study to assess reproductive health in men from the general population and to monitor changes in semen quality over time. Cross-sectional study of men from the general Danish population. Inclusion criteria were place of residence in the Copenhagen area, and both the man and his mother being born and raised in Denmark. Men with severe or chronic diseases were not included. Danish one-centre study. 4867 men, median age 19 years, included from 1996 to 2010. Semen volume, sperm concentration, total sperm count, sperm motility and sperm morphology. Only 23% of participants had optimal sperm concentration and sperm morphology. Comparing with historic data of men attending a Copenhagen infertility clinic in the 1940s and men who recently became fathers, these two groups had significantly better semen quality than our study group from the general population. Over the 15 years, median sperm concentration increased from 43 to 48 million/ml (p=0.02) and total sperm count from 132 to 151 million (p=0.001). The median percentage of motile spermatozoa and abnormal spermatozoa were 68% and 93%, and did not change during the study period. This large prospective study of semen quality among young men of the general population showed an increasing trend in sperm concentration and total sperm count. However, only one in four men had optimal semen quality. In addition, one in four will most likely face a prolonged waiting time to pregnancy if they in the future want to father a child and another 15% are at risk of the need of fertility treatment. Thus, reduced semen quality seems so frequent that it may impair the fertility rates and further increase the demand for assisted reproduction.
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Human semen quality in the new
millennium: a prospective cross-
sectional population-based study of 4867
men
Niels Jørgensen,
1
Ulla Nordstro
¨
m Joensen,
1
Tina Kold Jensen,
1
Martin Blomberg Jensen,
1
Kristian Almstrup,
1
Inge Ahlmann Olesen,
1
Anders Juul,
1
Anna-Maria Andersson,
1
Elisabeth Carlsen,
1,2
Jørgen Holm Petersen,
3
Jorma Toppari,
4,5
Niels E Skakkebæk
1
ABSTRACT
Objectives:
Considerable interest and controversy
over a possible decline in semen quality during the
20th century raised concern that semen quality could
have reached a critically low level where it might affect
human reproduction. The authors therefore initiated
a study to assess reproductive health in men from the
general population and to monitor changes in semen
quality over time.
Design: Cross-sectional study of men from the general
Danish population. Inclusion criteria were place of
residence in the Copenhagen area, and both the man
and his mother being born and raised in Denmark.
Men with severe or chronic diseases were not
included.
Setting: Danish one-centre study.
Participants: 4867 men, median age 19 years,
included from 1996 to 2010.
Outcome measures: Semen volume, sperm
concentration, total sperm count, sperm motility and
sperm morphology.
Results: Only 23% of participants had optimal sperm
concentration and sperm morphology. Comparing with
historic data of men attending a Copenhagen infertility
clinic in the 1940s and men who recently became
fathers, these two groups had significantly better
semen quality than our study group from the general
population. Over the 15 years, median sperm
concentration increased from 43 to 48 million/ml
(p¼0.02) and total sperm count from 132 to 151
million (p¼0.001). The median percentage of motile
spermatozoa and abnormal spermatozoa were 68%
and 93%, and did not change during the study period.
Conclusions: This large prospective study of semen
quality among young men of the general population
showed an increasing trend in sperm concentration
and total sperm count. However, only one in four men
had optimal semen quality. In addition, one in four will
most likely face a prolonged waiting time to pregnancy
if they in the future want to father a child and another
15% are at risk of the need of fertility treatment. Thus,
reduced semen quality seems so frequent that it may
impair the fertility rates and further increase the
demand for assisted reproduction.
To cite: Jørgensen N,
Joensen UN, Jensen TK,
et al. Human semen quality in
the new millennium:
a prospective cross-sectional
population-based study of
4867 men. BMJ Open
2012;2:e000990. doi:10.
1136/bmjopen-2012-000990
<
Prepublication history and
additional materials for this
paper are available online. To
view these files please visit
the journal online (http://dx.
doi.org/10.1136/
bmjopen-2012-000990).
Received 6 February 2012
Accepted 29 May 2012
This final article is available
for use under the terms of
the Creative Commons
Attribution Non-Commercial
2.0 Licence; see
http://bmjopen.bmj.com
For numbered affiliations see
end of article.
Correspondence to
Dr Niels Jørgensen; niels.
joergensen@rh.regionh.dk
ARTICLE SUMMARY
Article focus
-
A paper by Carlsen et al 20 years ago (BMJ
1992;305:609e13) raised controversy with
evidence of a decline in semen quality, and
several studies on semen quality in human
populations have followed.
-
There has been a lack of larger, prospectively
collected quality-controlled data on semen
quality in the general population.
Key messages
-
This study brings good and bad news.
-
Fifteen years monitoring of semen quality in men
of the general population indicated a slight
increase in both median sperm concentration
and total sperm count.
-
However, still only a fraction of the men (23%)
had optimal sperm concentration and sperm
morphology, and the median percentage of
abnormal spermatozoa was as high as 93%
with no sign of improvement during the study
period.
-
Approximately 15% of the men had a sperm
concentration at a level that would indicate a high
risk of needing future fertility treatment if they
want to father a child, and another 27% of the
men will be at risk of a prolonged waiting time to
pregnancy.
Strengths and limitations of this study
-
Large prospective study of semen quality among
men of the general population unselected with
regard to fertility.
-
Standardised inclusion and investigation proce-
dures.
-
Lack of historical, directly comparable data.
Jørgensen N, Joensen UN, Jensen TK, et al. BMJ Open 2012;2:e000990. doi:10.1136/bmjopen-2012-000990 1
Open Access Research
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INTRODUCTION
In the 1990s, a meta-analysis by Carlsen et al,
1
showing
a decline in human semen qual ity, initiated a heat ed
scientific debate. The discussion has recently resurfaced
in three papers in Epidemiology
2e4
and a news article in
Science.
5
The Carlsen paper, which was a review and meta-
analysis of internationally published data on semen
quality among healthy m en, suggested that there had
been a decline in sperm concentration and total sperm
count over a period of 50 years. Many were sceptical
about the results, and this prompted several researchers
to study trends in their own countries, mostly based on
data from semen banks or semen donor registries. The
resulting papers reported heterogeneous findings
(reviewed in Jouannet et al
6
and Merzenich et al
7
), with
some confirming a decreasing trend in semen quality,
and others not. In 2000, an updated comprehensive
meta-analysis was undertaken by Swan et al
8
that
confirmed the downward trend. During the same
period, there is strong evidence for a worldwide increase
in the incidence of testicular germ cell cancer, a disease
linked to decreased semen quality.
9e11
The background for the interest and controversy over
trends in semen quality was the obvious concern that
semen quality could have reached a critically low level
where it might affect fecundity (ie, the ability to repro-
duce). Therefore, since 1996, we have carried out
a prospective quality-controlled study of semen quality in
annual cohorts of men from the general Danish popu-
lation. A total of 4867 individuals have been included in
this study.
METHODS
The study population was men from the general Danish
population from the Copenhagen area examined in
1996e2010. For interpretation of the results, we
compared them to published data of two other studies
from the Copenhagen area: a recent study of fertile men
(male partners of pregnant women) examined in
1996e1998 by our group
12
and historical data of male
partners from infertile couples examined in 1939e1943
by Dr Richard Hammen.
13
Study population: men from the general population
examined in 1996e2010
In Denmark, all men, except those with severe or
ch
ronic diseases (<15%), are required to attend
a medical examination before being considered for
military service. Men are called upon to present them-
selves at th e age of 18e19 years, but some postpone this
examination until complet ion of their education. Men
attending the medical examinations are therefore
considered representative of the general population of
young men.
In collaboration with the military health authority,
men attending these medical examinations in the
greater Copenhagen area of Denmark were asked to
participate in the pre sent study, irrespective of whether
they were declared fit for military service or not. Further
inclusion criteria for this publication were: place of
residence in the greater Copenhagen area and both the
men and their mothers being born and raised in
Denmark. Those men who consented to participate were
given an appointment for examination at the Depart-
ment of Growth and Reproduction at Rigshospitalet
(Copenhagen, Denmark). Participants were instructed
to abstain from ejaculation for at least 48 h prior to
attendance at Rigshospitalet, where each man returned
a completed questionnaire, underwent a physical
examination and provided a semen sample. Participants
received a financial compensation (approximately V65).
Participants in this ongoing study have been included
since September 1996. Two of our previous publications
have directly focused on the semen quality level of men
examined from September 1996 to March 1998.
14 15
Other
publications have included information based on
subpopulations of men examined until the end of
2007,
16e35
but no previous trend analysis has been
performed on the material from the entire period.
Participants examined up until the end of December 2010
were included in the present publication, with 4901 men
fulfilling the inclusion criteria. The participation rate
among invited men ranged from 19% to 31%, with an
overall average of 24%. Data from 34 of the men were
excluded: 27 with previous or current use of anabolic
steroids, six who had previously received chemotherapy
for a malignant disease and one man who failed to deliver
a semen sample (he was later diagnosed with testosterone
deficiency due to a 46, XX-male karyotype). Thus, results
from the remaining 4867 men are reported here. The
study comprised annual cohorts of 240e543 men (median
276), 18e29 years of age (median 19). A detailed
description of the study population based on question-
naire information and results from the physical examina-
tion (see below) is summarised in table 1. The three types
of information is presented in table 1, ‘Been diagnosed as
having’, ‘Been treated for’ and ‘Has’ are based on ques-
tions phrased as ‘Has a doctor ever diagnosed you as
having.’, ‘Have you ever been treated for. and ‘Have
you ever.’, respectively. Within 3 months prior to partic-
ipation, 601 men (12%) had used medication, mainly
antibiotics, painkillers or asthma/allergy medicine.
Questionnaires
A standardised questionnaire was developed for this
study. In order to ensure the quality of the information
regarding previous conditions, the questionnaire was
sent to participants before their attendance at the
hospital, and they were asked to complete it beforehand
anddif possibledin collaboration with their parents.
The questionnaire included information on previous or
current diseases, including any known history of fertility
potential, and some lifestyle factors. The questionnaire
has been revised during the course of the study, mainly
with new questions being added, and the current
publication includes relevant information available from
all participants throughout the study.
2
Jørgensen N, Joensen UN, Jensen TK, et al. BMJ Open 2012;2:e000990. doi:10.1136/bmjopen-2012-000990
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Table 1 Physical appearance and self-reported information of young men from the general population in the Copenhagen area, Denmark
Investigation period
1996e2010, total (N[4867) 1996e2000 (N[1339) 2001e2005 (N[2254) 2006e2010 (N[1274)
Difference
between
the three
groups,
p Value
Mean (SD) Median (5e95) Mean (SD) Median (5e95) Mean (SD) Median (5e95) Mean (SD) Median (5e95)
Physical appearance
Age (years)* 19.4 (1.2) 19.0 (18.4e21.7) 19.6 (1.4) 19.0 (18.5e22.4) 19.3 (1.1) 18.9 (18.4e21.3) 19.4 (1.2) 19.0 (18.4e21.8) <0.0005{{
Height (m) 1.81 (0.06) 1.81 (1.71e 1.92) 1.81 (0.07) 1.81 (1.71e1.92) 1.81 (0.07) 1.81 (1.70e1.91) 1.82 (0.06) 1.82 (1.71e1.93) <0.0005{{
Weight (kg) 75.1 (11.5) 73.5 (59.4e 96.4) 75.2 (11.7) 73.6 (59.0e97.5) 74.9 (11.5) 73.3 (59.2e97.0) 75.5 (11.2) 74.1 (60.1e96.0) 0.15{{
BMI (kg/m
2
) 22.9 (3.1) 22.4 (18.7e28.8) 22.9 (3.2) 22.4 (18.8e28.9) 22.9 (3.2) 22.4 (18.7e29.0) 22.8 (3.1) 22.4 (18.7e25.6) 0.8{{
Testis size (ml)y 20 (5) 20 (13e28) 20 (5) 20 (12e 28) 20 (5) 20 (13e 28) 22 (5) 23 (14e 29) <0.0005{{
Testis size (ml), US 15 (4) 14 (9 e 22) 15 (5) 15 (9 e 24) 14 (4) 14 (9 e22) 14 (4) 14 (9 e21) <0.0005{{
Lifestyle
Cigarettes daily,
all men
4.1 (6.7) 0.0 (0.0e20.0) 5.0 (7.4) 0.0 (0.0e20.0) 3.9 (6.5) 0.0 (0.0e 20.0) 3.7 (6.2) 0.0 (0.0e18.0) 0.004{{
Cigarettes daily,
smokers only
9.9 (7.1) 10.0 (1.0e20.0) 11.7 (7.1) 10.0 (1.0e20.0) 9.9 (6.9) 10.0 (1.0e20.0) 8.1 (6.9) 7.0 (0.1e 20.0) <0.0005{{
Alcohol consumption
(units)z
14 (14) 11 (0 e 40) 13 (13) 11 (0 e 38) 14 (14) 11 (0 e37) 15 (16) 12 (0 e42) 0.1{{
Ejaculation
abstinence (hours)
81 (117) 63 (37e155) 86 (95) 63 (35e 168) 81 (137) 62 (38e 135) 77 (96) 63 (37e134) 0.1{{
%%%%
Taken medicationx 12.5 14.6 9.7 15.1 <0.0005{{
Smoker 41.7 42.5 39.1 45.4 0.001{{
Previous smoker 3.1 2.0 2.3 5.8 <0.0005{{
Never-smoker 55.2 55.6 58.6 48.7 <0.0005{{
Mother
smoked in
pregnancy
38.0 36.2 38.3 29.1 <0.0005{{
Been diagnosed as
having
Varicocele 0.6 0.5 0.7 0.4 0.4***
Epididymitis 0.3 0.3 0.5 0.2 0.3***
Sexual transmitted
disease{
4.3 2.2 4.6 6.2 <0.0005***
Cystitis 2.4 1.4 2.4 3.6 0.002***
Diabetes 0.02 0.0 0.04 0.0 0.6***
Thyroid disease 0.04 0.0 0.05 0.08 0.001***
Continued
Jørgensen N, Joensen UN, Jensen TK, et al. BMJ Open 2012;2:e000990. doi:10.1136/bmjopen-2012-000990 3
Human semen quality in the new millennium
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Table 1 Continued
Investigation period
1996e2010,
total (N[4867) 1996e2000 (N[1339) 2001e2005 (N[2254) 2006e2010 (N[1274)
Difference
between
the three
groups,
p Value
Mean (SD) Median (5e95) Mean (SD) Median (5e95) Mean (SD) Median (5e95) Mean (SD) Median (5e95)
Been treated for
Varicocele 0.4 0.0 0.7 0.4 0.004***
Testicular torsion 0.8 1.0 0.6 0.9 0.4***
Testicular cancer 0.02 0.0 0.0 0.1 0.2***
Cryptorchidism** 6.1 3.9 8.0 5.0 <0.0005***
Hypospadias 0.1 0.0 0.0 0.3 0.004***
Phimosis 3.9 5.4 2.7 4.6 <0.0005***
Inguinal hernia 3.4 3.8 4.8 0.5 <0.0005***
Has
Had cryptorchidismyy 8.3 4.4 11.2 6.9 <0.0005***
Experienced fertility
problemszz
0.6 1.7 0.2 0.2 <0.0005***
Caused a
pregnancyxx
6.4 7.4 5.6 6.8 0.08***
Subgroup 80.6 84.6 77.8 81.2 <0.0005***
*Calculated as difference between day of attendance in study and self-reported day of birth.
yMean of left and right testes size assessed by palpation. Information of testis size was missing for 3, 9 and 3 men from the 1st, 2nd and 3rd investigation period, respectively.
zSum of intake of beer, wine and strong alcohol recent week prior to participation in study.
xTaken any medication recent 3 months prior to participation in study.
{Chlamydia or gonorrhoea.
**Hormonal, surgical or combination.
yyNot born with both testicles in scrotum (irrespective of spontaneous descend, treatment or still cryptorchid).
zzEver had regular intercourse without use of contraception for at least 1 year, without partner became pregnant.
xxEver caused a pregnancy.
{{KruskaleWallis test.
***
c
2
test.
Subgroup: Men without adverse conditions ‘Been diagnosed as having.’, ‘Been treated for. or ‘Has.’. Those that have caused a pregnancy are also included, irrespective of any adverse
condition previously. See text for further explanation.
p Value: For comparison of results between the three study periods.
4 Jørgensen N, Joensen UN, Jensen TK, et al. BMJ Open 2012;2:e000990. doi:10.1136/bmjopen-2012-000990
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Semen samples
Semen samples were produced by masturbation. The
actual abstinence period was calculated from the self-
reported time of previous ejaculation and the time of
delivery of semen sample recorded by a technician. The
semen samples were produced in the privacy of a room
near the laboratory and kept at 378C.
Semen analysis was performed according to the WHO
guidelines.
36
In brief, semen volume was estimated by
weighing the collection tube with the semen sample and
subtracting the predetermined weight of the empty tube,
assuming that 1 ml semen ¼1 g. For sperm motility
assessment, 10 ml of well-mixed semen was placed on
a clean glass slide kept at 378C and covered with
a22322 mm coverslip. The preparation was placed on
the heated stage of a microscope at 378C and immediately
examined at 3400 magnification. The sperm were clas-
sified as progressively motile, locally motile or immotile.
For the assessment of the sperm concentration, the
samp
les were diluted in a solution of 0.6 mol/l NaHCO
3
and 0.4% (v/v) formaldehyde in distilled water. The
sperm concentration was subsequently assessed using
aBu
¨
rker-Tu
¨
rk haemocytometer (Paul Marienfeld GmbH
& Co. KG, Lauda-Ko
¨
nigshofen, Germany). Only sperm
with tails were counted.
Smears were prepared for morphological evaluation,
Papanicolaou stained and finally assessed according to
‘strict criteria’.
37
The laboratory participates in an external quality
control programme for sperm concentration assessment
as previously described.
15 38e40
The results did not show
any temporal trend in assessment level in the Copen-
hagen laboratory. Therefore, no adjustments according
to quality control results were needed. For the first 290
men included in our study, the weight of the empty
semen collection tubes was on average overestimated by
0.5 g, giving an underestimation of the semen weight by
0.5 g. The data on semen volum e among these men were
therefore corrected as follows: Corrected semen volume
¼ Observed semen volume +0.5 ml.
Physical examination
A physical examination of each participant was
per
formed on the day of delivery of his semen sample.
Tanner stage of pubic hair was recorded, and testicular
size was assessed, all examiners using the same type of
wooden orchidometer.
Comparison population: fertile men (partners of pregnant
women), examined in 1996e1998
From October 1996 to January 1998, our group also
ex
amined the semen quality of 349 fertile men (partners
of pregnant women); the results were published previ-
ously.
12
Pregnant women were approached during
routine visits at the antenatal care unit, and their partners
were invited to participate in the semen quality study. The
eligibility criteria were age 20e45 years at the time of
invitation, both the man and his mother being born and
raised in Denmark and conception of the current preg-
nancy by normal sexual relations (not as a result of
treatment for subfertility or infertility). Participation of
these men was similar to that of the men from the general
population: they answered a questionnaire, delivered
a semen sample and had a physical examination
performed. Both physical examination and semen anal-
ysis were performed in the same manner and in the same
laboratory as for men from the general population.
A description of the fertile men based on question-
naire information and on the results of the physical
examination has previously been published
12
and is
shown in table 2, which also includes additional infor-
mation to allow for a better comparison to the men from
the general population.
Comparison population: male partners from infertile
couples, examined in 1939e1943
Dr Richard Hammen published a doctoral thesis with
gro
und-breaking data on male infertility in 1944.
13
From
the Copenhagen area in Denmark, he investigated 925
men in ‘childless marriages’, defined as couples where at
least 1 year of regular coitus, without use of contracep-
tives, had not led to a successful pregnancy.
Hammen’s data origi nated from two cohorts (‘mate-
rial
I’ and ‘material II’) that he examined in 1939 e 1943.
Material I comprised 291 male partners attending the
Gynaecological Departmen t and Dispensary of the
Kommune Hospital, Copenhagen. Material II consisted
of 634 men who delivered basic information and semen
sample to the General Laboratory of National Health
Insurance Physicians, Copenhagen. Hammen stated that
information regarding duration of childlessness was
somewhat less reliable in this group than in material I
but concluded that only a few per cent of these men had
a duration of childlessness <1 year.
In his thesis, Hammen provided patient histories of
the study populations. The durations of childlessness in
the cohorts were 1e2 years (12.7% ), 2e3 years (22.7%)
and more than 3 years (64.4%). Secondary sterility was
ascertained in 26.8%, as 12.0% had children or abor-
tuses with other women and 14.8% with their current
partners.
The age distribution of the whole Hammen cohort
(materials I and II) was described as 2.7% <25 years,
72.6% 25e35 years, 22.3% 35 e 45 years and 2.4%
>45 years. Therefore, the median age seems to be
somewhere in early 30s, similar to that of the fertile men
we investigated in 1996e1998.
Some of the information obtained by Hammen was
similar to that obtained in our studies of men from the
general population and partners of pregnant women;
this is summarised in
table 2.
Information on medical
history was obtained from all men in material I, but only
from 548 men from material II. Thus, the figures
presented in table 2 are calculated based on information
from 839 men.
Hammen did not report height or weight, but noted
‘mode
rate or marked obesity’ in 6.6% of the men.
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Palpable changes in the epididymis were detected in
11.8%, abnormalities of the testis in 25.2%, cryptorchidism
of one or both testes in 5.2% and varicocele in 11.9%.
Previous venereal diseases were reported by 24.1% of
men in material I and 16.9% in material II. Other local
lesions involving the testes were reported (eg, hernia,
cryptorchidism) in 12.1% in material I and 4.0% in
material II. Hammen attributed the difference between
the two otherwise similar groups to erroneous informa-
tion given by the questioned patients in material II, as
they were not interviewed by Hammen directly. Previous
serious diseases (eg, pulmonary tuberculosis,
Table 2 Physical appearance and self-reported information of men from the Copenhagen area, Denmark
Study population
General population
1996e2010, total
(N[4867)
Fertile 1996e1998
(N[349)
Infertile couples
1939e1943
(N[839)
Mean (SD) Median (5e95) Mean (SD) Median (5e95)
Physical appearance
Age (years)* 19.4 (1.2) 19.0 (18.4e21.7) 31.5 (4.3) 30.8 (25.4e40.2) 73% 25e35 years
Height (m) 1.81 (0.06) 1.81 (1.71e1.92) 1.83 (6.2) 1.84 (1.73e1.94) e
Weight (kg) 75.1 (11.5) 73.5 (59.4e96.4) 83.0 (11.2) 82.0 (67.6e102.2) e
BMI (kg/m
2
) 22.9 (3.1) 22.4 (18.7e28.8) 24.6 (2.9) 24.3 (20.6e29.5) 6.6% ‘moderate
obese’
Testis size (ml)y 20 (5) 20 (13e28) 23 (4) 24 (15e30) e
Testis size (ml), US 15 (4) 14 (9e22) ee e
Lifestyle
Cigarettes daily, all men 4.1 (6.7) 0.0 (0.0e20.0) 4.5 (8.3) 0.0 (0.0e20) e
Cigarettes daily, smokers only 9.9 (7.1) 10.0 (1.0e20.0) 14.0 (8.9) 15.0 (0.5e30) e
Alcohol consumption (units)z 14 (14) 11 (0e40) 10 (9) 8 (0e30) e
Ejaculation abstinence (h) 81 (117) 63 (37e155) 81 (65) 64 (20e182) e
%% %
Taken medicationx 12.5 20.1 e
Smoker 41.7 32.5 e
Previous smoker 3.1 ee
Never-smoker 55.2 ee
Mother smoked in pregnancy 38.0 38.1 e
Been diagnosed as having
Varicocele 0.6 2.9 11.9
Epididymitis 0.3 2.6 1.9
Sexual transmitted disease{ 4.3 18.6 19.4
Cystitis 2.4 8.0 e
Diabetes 0.02 0.3 e
Thyroid disease 0.04 0.0 e
Been treated for
Varicocele 0.4 0.9 0.4
Testicular torsion 0.8 1.1
Testicular cancer 0.02 0.3 0.01
Cryptorchidism** 6.1 4.3 2.1
Hypospadias 0.1 0.0 0.0
Phimosis 3.9 ee
Inguinal hernia 3.4 6.0 1.5
Has
Had cryptorchidismyy 8.3 e >5.2
Experienced fertility problemszz 0.6 12.3 100.0
Caused a pregnancyxx 6.4 100.0 26.8
Infertile couples: 925 men delivered semen samples, however, patient history was only obtained on 839.
*Calculated as difference between day of attendance in study and self-reported day of birth.
yMean of left and right testes size assessed by palpation. Information of testis size was missing for 3, 9 and 3 men from the 1st, 2nd and 3rd
investigation period, respectively.
zSum of intake of beer, wine and strong alcohol recent week prior to participation in study.
xTaken any medication recent 3 months prior to participation in study.
{Chlamydia or gonorrhoea.
**Hormonal, surgical or combination.
yyNot born with both testicles in scrotum (irrespective of spontaneous descend, treatment or still cryptorchid). For the Hammen cohort similar
information was not obtained, but 5.2% of men were detected as having cryptorchidism when examined.
zzEver had regular intercourse without use of contraception for at least 1 year, without partner became pregnant.
xxEver caused a pregnancy.
6 Jørgensen N, Joensen UN, Jensen TK, et al. BMJ Open 2012;2:e000990. doi:10.1136/bmjopen-2012-000990
Human semen quality in the new millennium
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pneumonia and peritonitis) were recorded in 34.7% of
the cases. Present chronic conditions (diseases of the
stomach and intestines, especially peptic ulcer and
gastritis, neurasthenia, chronic otitis media, chronic
familial anaemia, osteomyelitis, bronchitis, diabetes
mellitus, epilepsy and heart disease) were recorded in
12.7% of the patients.
All men provided a semen sample. They had been
instructed to abstain from ejaculation for at least 3 days
prior to delivery of the semen sample, which was
produced throu gh interrupted coitus at home or by
masturbation in a private room in the hospital. Exact
information was requested about the period of ejacula-
tion abstinence.
The ejaculates were examined as soon as the specimen
was received. Semen was poured from the collection
beaker into a graduated container to assess volume. For
assessment of sperm concentration, the following
procedure was employed: ‘After thorough mixing of the
sperm in a shaking-machine or by hand, 0.1 cc. of sperm
is added to 1.9 cc. of the diluent (consisting of 190 cc. of
physiological salt solu tion, 7 cc. of a 1% methylene blue
solution and 3 cc. of absolute alcohol). The mixing takes
place in a dwarf-tube, containing a glass bead, which is
shaken for 5 m in in a shaking-ma chine or by hand. The
count is carried out with employment of a Bu
¨
rker-Tu
¨
rk
counting-chamber. All sperm heads are counted, also
loose heads. Loose tails are not counted’.
Statistical analysis in the present study
Means, medians, SDs, 5e95
percentiles and frequencies
were used for basic descriptions. The study subjects were
divided into three groups, depending on the investiga-
tion periods: 1996e2000, 2001e 2005 and 2006e2010.
Between-group differences for continuous variables were
tested by the non-parametric KruskaleWallis test.
Between-group differences for categorical variables were
tested with Pearson’s
c
2
test.
The main outcome variables were semen volume,
sperm concentration, total sperm count, percentage of
motile spermatozoa and percentage morphologically
normal spermatozoa. Temporal trend between investi-
gation periods were tested by multiple linear regressions
adjusted for confounders. Semen volume, sperm
concentration and total sperm count were best normal-
ised by a cubic root transformation before analysis to
correct for skewed distribution of residuals. The
percentages of motile spermatozoa were logit-trans-
formed. Percentages of morphologically normal sper-
matozoa were close to normally distributed and entered
the model untransformed. Ejaculation abstinence up to
96 h had an increasing effect on semen volume, sperm
concentration and total sperm count (all p values<0.05)
and was entered as a covariate in the regression analyses
of these variables, whereas it had no effec t on
morphology or motility. Increasing age had a non-
significant increasing effect on sperm concentration
(p¼0.8), but a significant increasing effect on semen
volume (p<0.0005), and was also entered as covariate.
Season of year was evaluated as a possible confou nder
for all the semen variables, and duration from ejacula-
tion to assessment was additionally evaluated as
a confounder for sperm motility. Both were non-signifi-
cant and therefore not included in the final models.
Differences in semen quality variables between men
from the general population and partners of pregnant
women were also tested by linear regressions corrected
for the same covariates as stated above. Differen ces in
distribution of sperm concentrations and total sperm
counts between men from the general pop-
ulation examined in 1996e2010 and male partners from
infertile couples examined in 1939e1943 were tested by
c
2
test.
A p value of <0.05 was considered statistically signifi-
cant. Analyses were performed using PASW GradPack
V.18.0 (SPSS Inc.).
RESULTS
Figure 1 shows sperm concentrations, total sperm counts
and percentages of morphologically normal sperma-
tozoa for each year of examination. Grouping results of
the 15 years into three 5-year periods showed a temporal
increase in the sperm counts (table 3). Men examined in
2006e2010 had higher median sperm concentration,
total sperm count and total number of morphologically
normal sperm count than men examined in the first 5-
year period. Similarly, men examined in 2001e2005
appeared to have higher counts than the previously
examined. Estimating the average linear increase over
the period confirmed the slightly increasing temporal
trends (p¼0.02, p<0.0005 and p¼0.013, respectively).
The median values indicated an increase in semen
volume, which was confirmed both when the three 5-year
periods were compared and when estimating the annual
linear increase (p<0.0005). The percentages of motile
and morphologically normal spermatozoa showed no
change over time.
As expected, some of the men had previously experi-
enced andrological problems, including cryptorchidism,
hypospadias, sexually transmitted diseases and/or other
signs or symptoms relating to the reproductive system
(
table 1).
As men with such diseases could be more
motivated to participate in the study, we performed
a subanalysis on the subgroup of 3921 men (80.6%) who
were without previous andrological abnormalities. The
main conclusion that impaired semen quality was
frequent remained robust. The results described here
are based on the entire group, whereas the results from
the subgroup are shown in appendix 1.
Comparison population: fertile men, examined in
1996e1998
Table 4 summarises the semen results of the 349 fertile
men examined previously
12
and the men from the general
population. The semen variables differed between these
groups, with highest semen volume, sperm concentration,
total sperm count, total number of morphologically
Jørgensen N, Joensen UN, Jensen TK, et al. BMJ Open 2012;2:e000990. doi:10.1136/bmjopen-2012-000990 7
Human semen quality in the new millennium
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normal spermatozoa and percentage of normal sperma-
tozoa in the fertile men (all p values <0.0005). Motility
variables were statistically lower for the fertile men.
Approximately 42% of the men from the general pop u-
lation had sperm concentrations below 40 million/ml
and 66% had <9% normal forms (figure 2). For 15% and
35% of men, the sperm concentration was below
15 million/ml and the percentage of normal spermatozoa
below 5%. For the fertile men, only 8% had a sperm
concentration below 15 mill/ml and 18% had <5%
normal forms. Only 23% of men from the general popu-
lation had the optim al sperm concentrations of more
than 40 million/ml and more than 9% normal forms, in
comparison to 42% of the fertile men.
Comparison population: male partners from infertile
couples, examined in 1939e1943
Figure 3 shows the distributions of sperm concentrations
and total sperm counts for our study group compared
with those of men from infertile couples in Denmark in
1940e1943 (Hammen cohort). As shown, our study
group had lower sperm counts than the historical cohort
(p<0.0005, for all comparisons).
DISCUSSION
In this large, prospective and well-controlled stud y of
semen quality of annual cohorts of young men from the
general population, statistically significant increases in
sperm concentration and total sperm counts over the
past 15 years were dete cted. However, it is of concern
that these men from the general population in the new
millennium had significantly lower sperm concentra-
tions and total sperm counts than recently examined
fertile men and men of a historical cohort of male
partners of infertile couples. Both sperm concentration
and sperm morphology measures according to strict
criteria are known to be informative semen measure-
ments for discriminating between fertile and infertile
men.
41
Therefore, there is reason to be concerned about
future fertility of young Danish men. Smaller cro ss-
sectional studies of men from the general populations in
other European countries have shown similar high
frequencies of men with poor semen quality.
38e40 42 43
Thus, poor semen quality seems to be a widespread
phenomenon. This interpretation is in line with the high
and increasing need of fertility treatment in Denmark.
44
We have considered whether immaturity of the men
(with a median age of 19 years) could account for the
findings. However, a 4-year longitudinal follow-up with
quarterly assessment of semen quality in a subgroup of
more than 150 of the men showed no significant change
over time in sperm concentration, total sperm count and
sperm morphology, suggesting that immaturity does not
explain our results.
45
It is also possible that our results
could be skewed by selection biases. However, during the
early stage of our project, we carried out a study on
blood samples from the majority of those men who did
not volunteer to provide semen samples (N¼195,
participation rate 79%) and showed that their repro-
ductive hormone levels including the spermatogenesis
markers follicle-stimulating hormone and inhibin-b were
very similar to those of the participants.
14
This suggests
that our results are not biased by selection. Furthermore,
our results hold true in the subgroup of men without
andrological events in their history as presented in
appendix 1. It is not likely that the detected temporal
trend in sperm count is due to intraobserver or inter-
observer variations. Our laboratory technicians partici-
pated in a quality control study of assessment of sperm
concentration, which did not indicate temporal changes
Figure 1 Semen parameters of Danish men from the general
population. Red bars show 25the75th percentiles with median
line. Whiskers show 5the95th percentiles. The sperm
concentration (A) and total sperm count (B) increased slightly
by year of examination. Percentage of morphologically normal
spermatozoa did not show any temporal trend (C).
8 Jørgensen N, Joensen UN, Jensen TK, et al. BMJ Open 2012;2:e000990. doi:10.1136/bmjopen-2012-000990
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in assessment levels. However, a longer observation
period is needed to corroborate or refute such a positive
tendency. Five observers did 97.6% of all morphology
assessments, among which a single observer assessed
91% of samples in the first 5-year period, 14% in the
second period and none in the last. One observer
assessed 14% of samples from the second period, but
none from the first or last period. This obser ver tended
to obtain 1% lower values than other observers (detailed
data not shown), which partly explains the lower number
of morphologically normal spermatozoa in the second 5-
year period. Assessment of semen volume was also
controlled and corrected when needed. Effects of
potential confounders of semen variables were investi-
gated and accounted for in the stat istical analyses.
Increasing duration of abstinence up to approximately
96 h had an increasing influence on semen volume,
sperm concentration and total sperm count, but no
effect on motility or morphology, which is in agreement
with our initial findings and with the results of oth er
semen quality studies of men from Europe.
38e40 42
From
pilot studies in the middle of 1990s, we know that
interobserver variation for motility assessment is of
significant importance
46
and difficult to eliminate. Our
results on numbers of motile sperms should therefore be
taken with som e caution.
The definition of normal semen quality has varied over
time
. Seventy years ago, the Danish standard for normal
sperm concentration set 60 million/ml as a lower cut-off
level.
13
However, the most recent WHO guid elines
adhere to common clinical practice, where the ‘normal’
reference range is defined as the one that covers 95% of
a population. The most recent WHO guidelines have
reduced the reference limits for sperm concentration
Table 3 Semen quality of 4867 young men from the general population in the Copenhagen area in Denmark
Mean (SD) Median (5e95)
p Values comparing
All periods
2001e2005 vs
2006e2010
1996e2000 vs
2006e2010
Semen volume (ml)
Investigation period 1996e 2010 3.4 (2.0) 3.2 (1.3e6.0)
Investigation period 1996e 2000 3.3 (1.5) 3.1 (1.2e5.8)
Investigation period 2001e 2005 3.3 (1.4) 3.2 (1.4e5.9)
Investigation period 2006e 2010 3.6 (3.1) 3.3 (1.3e6.3) 0.004 0.011 0.001
Sperm concentration (million/ml)
Investigation period 1996e 2010 60 (57) 45 (3 e 163)
Investigation period 1996e 2000 58 (55) 43 (3e167)
Investigation period 2001e 2005 60 (58) 45 (3e156)
Investigation period 2006e 2010 62 (55) 48 (3e169) 0.065 0.12 0.020
Total sperm count (million)
Investigation period 1996e 2010 193 (232) 143 (9e 529)
Investigation period 1996e 2000 185 (184) 132 (6e531)
Investigation period 2001e 2005 191 (241) 146 (8e508)
Investigation period 2006e 2010 206 (258) 151 (13e559) 0.002 0.015 0.001
Normal morphology (%)
Investigation period 1996e 2010 7.1 (4.9) 6.5 (0.5e16.0)
Investigation period 1996e 2000 7.3 (5.1) 7.0 (1.0e17.0)
Investigation period 2001e 2005 6.9 (4.8) 6.0 (0.5e15.5)
Investigation period 2006e 2010 7.5 (4.9) 7.0 (0.5e
16.0) 0.016 0.023 0.97
Total
normal spermatozoa (million)
Investigation period 1996e 2010 16.3 (23.9) 8.4 (0.0e57.4)
Investigation period 1996e 2000 16.5 (24.5) 7.9 (0.0 e 60.9)
Investigation period 2001e 2005 15.5 (22.6) 8.0 (0.0 e 53.8)
Investigation period 2006e 2010 17.9 (25.3) 9.8 (0.1 e 59.3) 0.040 0.012 0.076
Progressively motile (%)
Investigation period 1996e 2010 56 (17) 59 (23e 77)
Investigation period 1996e 2000 54 (17) 57 (22e75)
Investigation period 2001e 2005 57 (17) 60 (22e77)
Investigation period 2006e 2010 57 (16) 59 (25e79) <0.0005 0.30 0.005
Motile (%)
Investigation period 1996e 2010 65 (15) 68 (35e 83)
Investigation period 1996e 2000 65 (15) 68 (38e82)
Investigation period 2001e 2005 64 (15) 67 (35e82)
Investigation period 2006e 2010 65 (16) 68 (33e85) 0.17 0.09 0.71
5e95: 5e95 percentiles.
p Values: Obtained from regression analysis taking confounders into consideration.
Jørgensen N, Joensen UN, Jensen TK, et
al. BMJ Open 2012;2:e000990. doi:10.1136/bmjopen-2012-000990 9
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from 20 to 15 million/ml.
36
Reference limits based on
95% of the population may be rel evant in relation to
certain clinical tests (eg, levels of sodium or potassium in
serum) but are unsuitable for public health issues in
which secular changes may affect the whole population
(eg, obesity).
47
For trend analyses, our data on semen
quality of men examined during the past 15 years should
therefore rather be compared with data from the previous
generations of men. Unfor tunately, historic al data on
semen quality of men from the general population do not
exist. Other unique Danish semen data obtained by the
pioneer of modern Danish andrology, Dr Richard
Hammen, who studied semen quality of men 70 years
ago, exists.
13
His method for counting sperm concentra-
tion by the use of the Bu
¨
rker-Tu
¨
rk haemocytometer was
very similar to that used in our present investigations and
in accordance with the current recommen dations by the
WHO,
36
allowing for meaningful comparisons with our
new data. Interestingly, sperm num bers among men in
the Hammen study from the 1940s were significantly
higher than those in the present study, despite the fact
that the earlier sample was recruited among male part-
ners in infertile couples. This actually corroborates that
semen quality might have decreased temporarily as
suggested by the meta-analysis by Car lsen et al.
1
Whereas the historical data point to a temporal
decrease in sperm concentration and total sperm counts,
there is no such data to support a similar trend in the
percentages of normal spermatozoa in each ejaculate. A
trend may be difficult to detect because different criteria
for normality have been applied during the years. In our
study, we did not find any trend in sperm morphology
despite a slight increase in sperm numbers. However, it is
noteworthy that the median percentage of spermatozoa
with normal morphology was as low as 6.5%. In contrast
to our study, a decrease in the percentage of normal
spermatozoa was recently described in a Finnish study,
which also reported decreasing trends for sperm
concentration and total sperm counts.
40
Although only one spermatozoon is needed to fertilise
an egg, several studies have shown that the fertilising
ability diminishes if the sperm concentration is belo w
40e50 million/ml or if the percentage of normal sper-
matozoa is below 9%.
48e51
Approximately 42% of the
men from the general population had sperm concen-
trations below 40 million/ml and 66% <9% normal
forms. More sever e fertility problems may be present
when sperm concentration is below 15 million/ml and
the percentage of normal spermatozoa is <5%,
41 51
which was the cas e for 15% and 35% of the men from
the general Danish population, respectively. It is note-
worthy that only 8% and 18% of a group of fertile men in
a previous study of partners of pregnant women were
below these ‘cut-off’ levels. Spe rm concentration, total
sperm count and percentage of normal spermatozoa
were significantly lower in men from the general popu-
lation in comparison to fertile men. Only 23% of men
from the general population had the optimal sperm
concentrations of more than 40 million/ml and more
than 9% normal forms in comparison to 42% of the
fertile men.
Both clinical practice and animal studies suggest an
imp
ortant role of sperm morphology for conce ption
rates.
41 51
Human in vitro fertilisation studies also
suggest an important role of sperm morphology for
fertilisation rates, which become significantly lower if the
percentage of normal spermatozoa is below 5%. In men,
the number of morphologically normal spermatozoa is
usually reported to be below 10% and in animals above
50%. For example, breeding bulls and boars mos t often
have <10% abnormal spermatozoa,
52
and abnormalities
are often more subtle than the severe abnormalities
frequently seen in human samples. Even with relatively
low numbers of normal spermatozoa, humans may still
be able to reproduce. In contrast to wild animal species,
where survival of the species may depend on a very high
conception rate at each coitus, humans in monogamous
relationships are not dependent on immediate
Table 4 Semen quality of partners of pregnant women (fertile men) and young men from the general population from the
Copenhagen area in Denmark
Partners pregnant
women (N[349)
General population
Total group (N[4867) Subgroup (N[3921)
Mean (SD) Median (5e95) Mean (SD) Median (5e95) Mean (SD) Median (5e95)
Semen volume (ml) 3.8 (1.7) 3.6 (1.1e 6.7) 3.4 (2.0) 3.2 (1.3e6.0) 3.4 (2.1) 3.2 (1.3e5.9)
Sperm concentration
(million/ml)
77 (66) 61 (10e207) 60 (57) 45 (3e163) 61 (57) 47 (4e166)
Total sperm count (million) 276 (240) 215 (32e795) 193 (232) 143 (9e529) 197 (231) 146 (10e531)
Normal morphology (%) 9.3 (5.0) 8.5 (2.0e 18.5) 7.1 (4.9) 6.5 (0.5e16.0) 7.2 (4.9) 6.5 (0.5e16)
Total normal spermatozoa
(million)
30 (37) 18 (1 e 111) 16 (24) 8 (0e57) 17 (24) 9 (0.1e59)
Progressive motile (%) 51 (15) 52 (25e72) 57 (16) 60 (24e77) 57 (16) 60 (24e77)
Motile (%) 60 (12) 61 (40e79) 65 (15) 68 (35e 83) 65 (15) 68 (37e83)
5e95: 5e95 percentile.
Subgroup: Men without adverse conditions ‘Been diagnosed as having.’, ‘Been treated for. or ‘Has. as described in table 1. Those that
have caused a pregnancy are also included, irrespective of any adverse condition previously. See table 1 and text for further explanation.
10 Jørgensen N, Joensen UN, Jensen TK, et al. BMJ Open 2012;2:e000990. doi:10.1136/bmjopen-2012-000990
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reproductive success to the same degree. In fact, the
current definition of couple infertility in most national
health systems is ‘more than 1 year of regular, unpro-
tected sexual relationship without pregnancy’.
53
In other
words, absence of pregnancy in spite of regular coitus
during up to 12 ovulation periods can be considered
‘normal’ from a clinical point of view. However, fecun-
dity m ay still be reduced compared to couples where
conception occurs immediately after unpr otected inter-
course during the first cycle.
In conclusion, our large prospective study of men of
the
general population supports previous suggestions of
a temporal decrease in semen quality, but it also indi-
cated a recent smal l increase in sperm concentration
and total sperm count. Follow-up studies are needed to
detect if the upward trend is a real biological phenom-
enon or merely random variation. It is noteworthy that
only one in four men had optimal semen quality from
Figure 2 Distributions of sperm counts and morphologically
normal spermatozoa in Danish men from the general
population and fertile Danish men (partners of pregnant
women). All men had durations of ejaculation abstinence
above 48 h. Sperm concentration (A) total sperm counts (B)
and percentages of morphologically normal spermatozoa (C)
were lower in men from the general population.
Figure 3 Distributions of sperm counts in Danish men from
the general population, examined from 1996 to 2010 and
Danish men examined in an infertility clinic in the 1940s. All
men had durations of ejaculation abstinence above 48 h.
Sperm concentration (A) and total sperm counts (B).
Jørgensen N, Joensen UN, Jensen TK, et al. BMJ Open 2012;2:e000990. doi:10.1136/bmjopen-2012-000990 11
Human semen quality in the new millennium
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a fecundity perspective. Approximately 25% had
a reduced quality compatible with prolonged waiting
time to pregnancy, and another 15% had so severely
impaired quality that they have a high risk of the need
for fertility treatment to become biological fathers.
Author affiliations
1
University Department of Growth and Reproduction, Rigshospitalet,
University of Copenhagen, Copenhagen, Denmark
2
The Fertility Clinic Rigshospitalet, Copenhagen, Denmark
3
Institute of Public Health, Department of Biostatistics, University of
Copenhagen, Copenhagen, Denmark
4
Department of Physiology, University of Turku, Turku, Finland
5
Department of Paediatrics, University of Turku, Turku, Finland
Contributors Substantial contributions to conception and design: NJ, TKJ,
A-MA, JT and NES. Acquisition of data: NJ, UNJ, TKJ, MBJ, IAO, AJ and EC.
Analysis of data: NJ, UNJ, KA, JHP and NES. Interpretation of data: all authors.
Drafting the article: NJ, UNJ and NES. Revising the article critically for
important intellectual content: all authors. Final approval of the version to be
published: all authors.
Funding This study has been supported economically by several grants: the
European Union (contract numbers BMH4-CT96-0314,
QLK4-CT-1999e01422, QLK4-CTd2002e00603 and most recently FP7
2007e2013, DEER Grant agreement no. 212844), the Danish Research
Council (grants numbers 9700833 2107-05-0006), the Danish Agency for
Science, Technology and Innovation (Grant number 271070678),
Rigshospitalet (Grant number 961506336), the University of Copenhagen
(Grant number 211-0357/07-3012), the Danish Ministry of Health and the
Danish Environmental Protection Agency, A.P. Møller and wife Chastine
McKinney Møllers foundation and Svend Andersens Foundation. The funding
organisations played no role in the design and conduct of the study; in
collection, management, analysis and interpretation of the data; or in the
presentation, review or approval of the manuscript.
Competing interests None.
Ethics approval The local Science Ethical Committee had approved the study
(June 1996, the Science Ethical Committee for the Copenhagen and
Frederiksberg municipalities, reference number KF01-117/96, and most
recently June 2011, the Capital Region of Denmark, reference number
H-KF-289428), and all participants had given their informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement There are no additional data available.
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APPENDIX 1
Semen results for men from the general population have been
summarised in
figure 1 of
the main text. Online table A1 summarises
the semen results for the subgroup of men without previous andro-
logical abnormalities as well as p values for differences between the
three 5-year periods (similar to table 2, which described the entire
study population in the main text). Men examined in 2006e2010 had
higher median sperm concentration, total sperm count and total
number of morphologically normal spermatozoa than men examined in
the first 5-year period. In analyses using year of examination as
a continuous variable, the significant trends were also confirmed for the
subgroup: p¼0.02, p¼0.001 and p¼0.004.
Table 3 in the main text summarised the semen results of the 349
fertile men examined previously.
12
The semen variables differed
between these men and men from the general population, with highest
semen volume, sperm concentration, total sperm count, total number of
morphologically normal spermatozoa and percentage of normal sper-
matozoa in the fertile men. These differences were all highly significant
at p<0.0005, irrespective of the comparisons being made between the
fertile men and the entire study group of men from the general popula-
tion; the subgroup of men from the general population without any
andrological event in their history examined in 1996e2010 or the smaller
subgroup examined in 2006e2010. The differences are shown in online
figure A1.1 and A1.2, which show the distributions of sperm concentra-
tions, total sperm count and number of morphologically normal sper-
matozoa for men from the general population (red bars), and partners of
pregnant women (green bars). For these variables, we show data based
on the entire study population, data based on only those with an ejac-
ulation abstinence of at least 48 h, data based on only those having an
ejaculation abstinence period of at least 48 h and without any andro-
logical event in their history (subgroup) and finally data based on the
same subgroup of men from the general population examined in the
period 2006e2010. The tendency that men from the general population
have lower semen volume, sperm concentration, total sperm count, total
number of morphologically normal spermatozoa and percentage of
normal spermatozoa than partners of pregnant women is seen irre-
spective of which of the four groupings are evaluated.
Online figure A2 shows the distributions of sperm concentrations and
total
sperm counts for the men from the general population (grouped as
in online figure A1) compared with men from infertile couples in
Denmark, 1940e1943.
13
Here, too, it can be seen that the recent
general population has lower sperm counts than the historical cohort
(p<0.0005, for all comparisons).
PAGE fraction trail=12.75
Jørgensen N, Joensen UN, Jensen TK, et al. BMJ Open 2012;2:e000990. doi:10.1136/bmjopen-2012-000990 13
Human semen quality in the new millennium
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doi: 10.1136/bmjopen-2012-000990
2012 2: BMJ Open
Niels Jørgensen, Ulla Nordström Joensen, Tina Kold Jensen, et al.
population-based study of 4867 men
millennium: a prospective cross-sectional
Human semen quality in the new
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... Fortuitously, data of the levels of multiple phthalate metabolites and bisphenols are available in spot urine samples from young Danish men taken in 2009 (Frederiksen et al. 2020). The characteristics of the study population and sampling strategy are described in detail (Jørgensen et al., 2012, Frederiksen et al., 2020. The data were supplemented by additional analyses for paracetamol (reported here). ...
... For the present assessment, we utilized the results of analyses in samples taken in 2009 (n = 98). The details of sampling strategy, sample handling and storage and the features of study participants are described in detail by Jørgensen et al. (2012) and Priskorn et al. (2018) and the details regarding selection of samples for this specific sub-study are described in Frederiksen et al. (2020). ...
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Background Semen quality in men continues to decline in Western countries, but the contours of the issue remain obscure, in relation to contributing chemicals. Objectives To obtain more clarity about the chemicals that drive the deterioration of semen quality, we conducted a mixture risk assessment based on European exposures. Methods We included chemicals capable of affecting semen quality after prenatal exposures, among them androgen receptor antagonists, substances that disrupt prostaglandin signalling, suppress testosterone synthesis, inhibit steroidogenic enzymes or activate the aryl hydrocarbon receptor. We employed the Hazard Index approach (HI), based on risk quotients of exposures in Europe and reference doses for reductions in semen quality. By summing up the risk quotients of the 29 chemicals included in the assessment we examined fold-exceedances of “acceptable” mixture exposures relative to an index value of 1. For bisphenols A, F, S, phthalates DEHP, DnBP, BBzP, DiNP, n-butyl paraben and paracetamol we relied on biomonitoring studies in which these 9 chemicals were measured together in the same subjects. This allowed us to construct personalised Hazard Indices. Results Highly exposed subjects experienced combined exposures to the 9 chemicals that exceeded the index value of 1 by more than 100-fold; the median was a 17-fold exceedance. Accounting for median background exposures to the remaining 20 chemicals added a Hazard Index of 1.39. Bisphenol A made the largest contribution to the HI, followed by polychlorinated dioxins, bisphenols S and F and DEHP. Eliminating bisphenol A alone would still leave unacceptably high mixture risks. Paracetamol is also a driver of mixture risks among subjects using the drug. Conclusions Tolerable exposures to substances associated with deteriorations of semen quality are exceeded by a large margin. Bisphenols, polychlorinated dioxins, phthalates and analgesics drive these risks. Dedicated efforts towards lowering exposures to these substances are necessary to mitigate risks.
... were assessed according to WHO guidelines with the modifications described by Jørgensen et al. 16 In brief, sperm motility was evaluated by adding 10 µl semen to a heated (37 • C) glass slide, which was immediately examined on a heated (37 • C) stage of a microscope and spermatozoa classified as progressive motile or non-progressive/immotile. Aliquots of raw semen corresponding to 3 × 10 6 cells were immediately used for the assessment of acrosomal status and viability. ...
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Background: Couples increasingly experience infertility and seek help from assisted reproductive techniques to become pregnant. However, 5%-15% of the couples that are selected for in vitro fertilisation (IVF) experience a total fertilisation failure (TFF), where no zygotes develop despite oocytes and semen parameters appear to be normal. We hypothesise that TFF during IVF could be related to improper membrane fusion of gametes. Objective: To investigate the membrane integrity and fusion proteins in spermatozoa from men in couples experiencing TFF. Materials and methods: A total of 33 infertile couples, 17 of which experienced TFF during IVF and 16 matched control couples with normal IVF fertilisation rates, were selected and the men re-called to deliver an additional semen sample. Proteins involved in gamete membrane fusion on spermatozoa (IZUMO1, SPESP1 and Syncytin-1) as well as O-glycosylation patterns (Tn and GALNT3), were investigated by immunofluorescence. The DNA fragmentation index, acrosomal integrity and viability of spermatozoa were determined by flow and image cytometry. Results: No significant changes in the expression of GALNT3, Tn and Syncytin-1 were observed between the TFF and control groups. The fraction of spermatozoa expressing SPESP1, the median IZUMO1 staining intensity, and the percentage of viable acrosome-intact spermatozoa were significantly lower in the TFF group compared to controls. Furthermore, following progesterone-induced acrosomal exocytosis, a significant difference in the fraction of spermatozoa expressing SPESP1 and the median IZUMO1 staining intensity were observed between the control and TFF group. Discussion and conclusion: Our results indicate that acrosomal exocytosis, IZUMO1 and SPESP1 expression in spermatozoa could play a crucial role in achieving fertilisation during IVF. However, the size of our cohort was quite small, and our results need to be validated with quantitative methods in larger cohorts.
... Учитывая возрастающие риски, связанные с воспроизводством населения, в различных странах проводятся популяционные исследования мужской фертильности, которые привели к выводу, что регион проживания и этническая принад-лежность являются важными детерминантами мужской фертильности [7][8][9][10][11][12][13][14]. Считается, что изменчивость параметров мужской фертильности могут определять экологические (загрязнение окружающей среды), социальные (индивидуальный образ жизни) и генетические факторы, однако 30-40% мужского бесплодия остается с невыясненными причинами и обозначается как идиопатическое бесплодие [15]. ...
... kg/m 2 ), and morbidly obese (MOB; BMI ≥40 kg/m 2 ) a threatened status of male fertility. However, these results face opposing reports from other authors, who did not find such negative trends [15,16,[65][66][67]. ...
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Purpose To assess the possible variations in semen quality during the last 20 years in Córdoba, Argentina, and to identify possible causal lifestyle or genitourinary factors. Methods Retrospective study of 23,130 patients attending an andrology laboratory. The 20-year period (2001–2020) was divided into four quinquenniums. Seminal parameters (sperm concentration, motility, morphology, viability, and membrane functional integrity) were classified as normal or abnormal according to WHO, and results were expressed as percentage of patients abnormal for each parameter per quinquennium. In addition, the percentage of patients per quinquennium exposed to the different risk factors (daily alcohol and/or tobacco consumption; occupational exposure to heat or toxics; history of parotitis or varicocele; and high body mass index, BMI) was reported. Results Patients included in our study did not show impairment in seminal quality over time. Beyond a transient decrease in normozoospermia in the second and third quinquennium, possibly explained by a parallel increase in teratozoospermia, other important parameters of the spermogram did not change. In fact, abnormalities in sperm concentration (oligozoospermia), total sperm count, viability and response to hypoosmotic test showed a decreasing trend over time. On the other hand, parotitis, varicocele, morbid obesity and regular exposition to heat/toxics were the factors more frequently associated with semen abnormalities; the last two increased their frequency over the study period. Conclusion The population included in this study did not show a clear impairment in semen quality during the last 20 years. The decreasing patterns found were associated with high BMI and exposure to heat/toxics.
... Another study conducted a retrospective analysis of 119,972 men looking at total motile sperm count trends from 2002 to 2017 and revealed a decline of approximately 10% over the past 16 years (Tiegs et al., 2019;Mann et al., 2020). Jorgensen et al. (2012) showed an increasing trend in sperm concentration and total sperm count in 4,867 young men in Copenhagen, Denmark (Huang et al., 2017). Despite the decline in male fertility continues unabated, recent high-quality studies have demonstrated that there is indeed a decline in sperm parameters and have shown possible links for this decline in sperm parameters such as obesity, diet, and environmental toxins (Mann et al., 2020). ...
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Plants have major role not only in maintaining the continuity of the environment but also in close association with human beings in day-today life. People use many plants as their food as well as to cure many of their health issues. But some plants are also there in nature which proves their effectiveness in dose dependent manner. In today's world, both toxic chemicals in the environment and phyto-products are affecting man's reproductive machinery by producing unhealthy sperms. Taking phyto-products into consideration, some are very effective in ameliorating the reproductive health of males and some act as toxic to the reproductive system. Lysimachia ramosa is a plant which is consumed as vegetable (in boiled condition) against worm infection. Kaempferol derivative is isolated from leaves of plant which is the active anthelmintic component in the plant. Before considering this component as potential candidate for health care, its adverse effects, particularly of antifertility effect, if any, should be investigated. Therefore this study has been undertaken to check effects of kaempferol derivative on its male consumer's reproductive system, taking wistar rats as animal model. The experiment was performed following OECD 407 guideline. 250 mg, 500 mg and 1000 mg kaempferol derivative per kg b.w. of animals were selected for the experimental animals and dosed continuously for 28 days. On 29 th day, animals were sacrificed, testes along with cauda-epididymis were isolated and tested for gonado-somatic indices, sperm count, motility, viability and morphology abnormality of sperms. Seminiferous tubules where sperms are generated were also studied with the help of haematoxylin-eosin staining technique and scanning electron microscopy. Results show that at 250 mg per kg b.w. of the component, it exerts beneficiary effect to the reproductive system, however, at highest dose i.e. 1000 mg per kg b.w. the component affects the reproductive health in a negative way. Therefore the active component is considered to be safe for future study below 500 mg/kg b.w.
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Purpose: To examine trends of population-level semen quality over a 20-year period. Materials and methods: We performed a retrospective review of data from the andrology lab of a high volume tertiary hospital. All men with semen samples between 2000 and 2019 were included and men with azoospermia were excluded. Semen parameters were reported using the World Health Organization (WHO) 4th edition. The primary outcome of interest was changes in semen parameters over time. Generalized least squares (GLS) with restricted cubic splines were used to estimate average-monthly measurements, adjusting for age and abstinence period. Contrasts of the estimated averages based on GLS between the first and last months of collection were calculated. Results: A total of 8,990 semen samples from subfertile non-azoospermic men were included in our study. Semen volume decreased over time and estimate average at the beginning and end were statistically different (p<0.001). Similarly sperm morphology decreased over time, with a statistically significant difference between estimated averages from start to finish (p<0.001). Semen pH appeared to be increasing over time, but this difference was not significant over time (p=0.060). Sperm concentration and count displayed an increase around 2003 to 2005, but otherwise remained fairly constant over time (p=0.100 and p=0.054, respectively). Sperm motility appeared to decrease over time (p<0.001). Conclusions: In a large sample of patients presenting to a single institution for fertility assessment, some aspects of semen quality declined across more than two decades. An understanding of the etiologies and driving forces of changing semen parameters over time is warranted.
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Objective To determine the semen quality and reproductive hormones of men conceived by in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) compared with men conceived without assisted reproductive technology (ART). Design Cohort study. Setting IVF centers in Victoria and the Western Australian Raine Study. Patient(s) Men conceived with IVF/ICSI and men conceived without ART aged 18–25 years. Intervention(s) Clinical review. Main Outcome Measure(s) The primary outcome was the prevalence of severe oligozoospermia (sperm concentration, <5 million/mL). The secondary outcomes were total sperm count, total and progressive motility, total motile count, normal morphology, and serum testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Results There was no difference in the prevalence of severe oligozoospermia between 120 men conceived with IVF/ICSI and 356 men conceived without ART (9% vs. 5.3%). Men conceived with IVF/ICSI had similar sperm concentration, total sperm count, and total motile count but lower mean total (55.3% vs. 60.6%) and progressive (44.7% vs. 53.9%) sperm motility with higher mean normal morphology (8.5% vs. 5.4%). Differences in progressive motility (ß, -9.9; 95% confidence interval [CI], -16.7 − -3.0), normal morphology (ß, 4.3; 95% CI, 3.0–5.7), and proportion with abnormal morphology (adjusted odds ratios, 0.1; 95% CI, 0.04–0.5) remained significant after adjusting for confounders. Men conceived with IVF/ICSI had lower mean FSH (3.3 IU/L) and LH (3.9 IU/L) levels and higher mean testosterone levels (19.1 nmol/L) than controls (4.2 IU/L, 11.0 IU/L, and 16.8 nmol/L). Conclusion This study of men conceived with IVF/ICSI found similar sperm output to men conceived without ART. Overall, the results are reassuring.
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Background: Previous meta-analyses concluded that there is a decline in sperm parameters over time. This conclusion might be incorrect due to inherent biases or focusing only on a single parameter - sperm concentration. Objective: To study trends in sperm parameters over the past 20 years using data from the trials that defined the reference ranges of the World Health Organization manual. Materials and methods: Retrospective evaluation of the data used to define the World Health Organization reference ranges. The data from 11 studies, including 3589 participants between 1996 and 2016, were divided into three period groups based on the decade of study. Differences in semen parameters' distribution were presented in boxplot. p-values were calculated by the Kruskal-Wallis rank-sum test followed by Dunn post hoc test. Analyses were conducted using the R programming language. Results: A small decrease was noted in mean sperm concentrations (88.1 million/ml, 87.6 million/ml, and 77.2 million/ml for the first, second, and third decades, respectively) (p < 0.01). However, the 5th percentile of sperm concentration for the third decade was higher than the first or second decades (18 million/ml versus 14.9 million/ml and 15 million/ml, respectively). No significant differences were noted in progressive motility over the years (p = 0.32). The percent of morphologically normal sperm decreased between the first (24.2%) and the second (12.6%) periods of the study (p < 0.001) and then increased in the third decade (14.2%) (p < 0.01). Total motile sperm count (TMC) declined between the second and third decades (189 million and 153.9 million, respectively, p < 0.001), at levels unlikely to decrease fertility. However, the 5th percentile of the TMC remained stable at 24.9, 20.8, and 20.6 million, for the first, second, and third decades respectively (p = 0.36). Discussion and conclusion and relevance: Trends in sperm parameters over the last three decades do not seem to be clinically significant.
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Concern about the effect of environmental changes on male reproductive health has grown in recent years to become a major preoccupation in some developed countries. A possible decline in human sperm concentration was suggested in the early seventies following studies in the US. In 1992 a meta-analysis of 61 articles published by Carlsen et al. concluded that the mean sperm count of healthy men had declined by 1% per year over the previous 50 years. From 1995 and onwards, some retrospective, longitudinal analyses of the sperm count of fertile or infertile men contradicted this while others did not. The demonstration of a geographical variation in sperm concentration, between and within countries or regions, appears to be less controversial. The amplitude of the difference observed cannot only be explained by methodological or confounding factors, and must to some extent be attributed to ethnic, genetic or environmental factors. As many of the published studies suffer from imprecision regarding the description of population characteristics and confounding factors, and were not designed with controlled and standardised methodology, the debate remains open. Prospective studies in well-defined cohorts of men in various populations are required to evaluate the potential effect of external factors on male reproductive health. These studies should not be limited to the analysis of sperm concentration, as this may not be the best biomarker of testis function and human fertility.
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A possible association between the polymorphic CAG repeat in the DNA polymerase gamma (POLG) gene and the risk of testicular germ-cell tumours (TGCT) was investigated in this study. The hypothesis was prompted by an earlier preliminary study proposing an association of the absence of the common 10-CAG-long POLG allele with testicular cancer as well as previously reported in some European populations' association with male subfertility, which is a condition carrying an increased risk of TGCT. The number of CAG repeats in both POLG alleles was established in 243 patients with TGCT and in 869 controls by the analysis of the genomic DNA fragment. A significantly higher proportion of men homozygous allele of other than the common 10 CAG repeats was found among the patients with TGCT in comparison to the controls (4.9% versus 1.3%, respectively, P = 0.001). The vast majority of the homozygous patients had a seminoma (11 of 12; 97%), despite that only about half (55%) of the studied patients had this tumour type. The findings indicate that the POLG polymorphism may be a contributing factor in the pathogenesis of TGCT particularly in seminoma, but the mechanisms remain to be elucidated.
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Male reproductive function seems to have deteriorated considerably during the past 4–5 decades. However, studies of the reproductive function in unselected populations have not previously been reported. As the large majority of young men in Denmark are subjected to a compulsory medical examination for military service, this provided a unique opportunity to study the reproductive function in an unbiased population. Altogether 891 young men delivered a blood sample in which reproductive hormones were measured. From 708 of these men data were also obtained on semen quality and testis size. The median sperm concentration was 41 × 106/ml (mean 57.4 × 106/ml). Men with ejaculation abstinence above 48 h had slightly higher sperm concentrations (median 45 ×106/ml, mean 63.2 × 106/ml), but even in this subgroup, 21 and 43% respectively had sperm counts below 20 × 106/ml and 40 × 106/ml. Among men with no history of reproductive diseases and a period of abstinence above 48 h, as many as 18 and 40% respectively had concentrations below 20 and 40 × 106/ml. Sperm counts were positively correlated with testis size, percentage normal spermatozoa and inhibin B, and negatively correlated with percentage immotile spermatozoa and follicle stimulating hormone. Possible causes for this high frequency of young men with suboptimal semen quality are obscure and need to be explored. Whether these findings apply for young male populations of comparable countries remains to be seen.
Article
Between 1996 and 1999, the authors invited all young men from five European countries who were undergoing compulsory medical examination for possible military service to participate in a study on male reproductive health. The participation rate was 19% in two cities in Denmark (n = 889), 17% in Oslo, Norway (n = 221), 13% in Turku, Finland (n = 313), 14% in Kaunas, Lithuania (n = 157), and 19% in Tartu, Estonia (n = 190). Each man provided a semen sample, was examined by a physician, and, in collaboration with his mother, completed a questionnaire about general and reproductive health, current smoking habits, and exposure to smoking in utero. After adjustment for confounding factors, men exposed to smoking in utero had a reduction in sperm concentration of 20.1% (95% confidence interval (CI): 6.8, 33.5) and a reduction in total sperm count of 24.5% (95% CI: 9.5, 39.5) in comparison with unexposed men. Percentages of motile and morphologically normal sperm cells were 1.85 (95% CI: 0.46, 3.23) and 0.64 (95% CI: –0.02, 1.30) percentage points lower, respectively, among men exposed in utero, and exposed men had a 1.15-ml (95% CI: 0.66, 1.64) smaller testis size. The associations were present when data from the study centers were analyzed separately (though not in Lithuania, where only 1% of mothers smoked during pregnancy), although the strength of the association varied. Maternal smoking may have longterm implications for the reproductive health of the offspring. This is another good reason to advise pregnant women to avoid smoking. pregnancy; prenatal exposure delayed effects; semen; smoking; spermatozoa; sperm count
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The decline in semen quality has been the subject of an animated debate. A recent prospective study now irrefutably shows a decline in semen quality in men from Finland, a country that previously boasted good semen quality. Semen quality has, in some countries, reached a level where a considerable fraction of young men are at risk of fertility problems. Impaired semen quality, testicular cancer, cryptorchidism and hypospadias are risk factors for each other, and the testicular dysgenesis syndrome (TDS) has been put forward to explain the observations. This syndrome implies that the four disease entities share the same patho-physiological etiology caused by disturbed testicular development in early fetal life. It seems likely that the rapid rise in TDS-associated conditions can, at least partly, be explained by environmental factors. Animal studies provide strong evidence that manmade chemicals can disrupt the hormone dependent pathways responsible for fetal gonadal development, subsequently leading to TDS-like symptoms. In humans, fetal exposure to endocrine disrupting substances may play a role, although genetic factors are probably also involved. Recent studies indicate that exposure to endocrine disrupters also in adulthood may affect semen quality and reproductive hormones. Causal relationships are inherently difficult to establish in humans, and a clear connection between the disorders and specific toxicants has not been established. It seems likely that the cumulative effects of various low-dose exposures to endocrine disrupters in our environment are responsible for the adverse effects in the male reproductive system. Semen quality may be the most sensitive marker of adverse environmental exposures, and we suggest that standardized surveillance studies of semen quality are continued or initiated to monitor the combined effects of various preventive actions.
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A scientific scuffle over the sperm counts of Danish men has highlighted a tricky question: To whom do data belong? A controversial study published in 1992 suggested that sperm counts worldwide had decreased by nearly half between 1938 and 1990, but since then, scientists have struggled to come up with data of the quality needed to resolve the contentious issue. Last week, in what its editor acknowledges was an unusual move, the journal Epidemiology published a commentary and an editorial on new sperm count data that had not been submitted to it, nor had they been published elsewhere by the researchers who collected them.