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Received: 26 August 2020    Revised: 25 October 2020    Accepted: 18 November 2020

DOI: 10.1111/andr.12947

ORIGINAL ARTICLE

Male factor infertility trends throughout the last 10 years:

Report from a tertiary-referral academic andrology centre

Giuseppe Fallara1,2  | Walter Cazzaniga1,2 | Luca Boeri1,3 | Paolo Capogrosso1,4  |

Luigi Candela1,2 | Edoardo Pozzi1 | Federico Belladelli1,5  | Nicolò Schifano1,2 |
Eugenio Ventimiglia1  | Costantino Abbate1 | Enrico Papaleo5,6 | Paola Viganò5,6 |
Francesco Montorsi1,2 | Andrea Salonia1,2

1
Division of Experimental Oncology/Unit
of Urology, URI, IRCCS Ospedale San Abstract
Raffaele, Milan, Italy
Background: Trends of male factor causes of couples' infertility over time have been
2
University Vita-Salute San Raffaele,
Milan, Italy
poorly investigated.
3
Department of Urology, Foundation Objective: We investigated trends in the causes of pure male factor infertility (MFI)
IRCCS Ca’ Granda – Ospedale Maggiore throughout the last 10 years in a tertiary-referral academic andrology center.
Policlinico, University of Milan, Milan, Italy
4 Material and Methods: Baseline characteristics at first presentation from a cohort of
Department of Urology and Andrology,
Ospedale di Circolo and Macchi 1647 consecutive male factor infertility patients belonging to primary infertile couples
Foundation, Varese, Italy
5
between 2008 and 2018 have been comprehensively collected over time. Seven major
Division of Genetics and Cell Biology,
Reproductive Sciences Laboratory, IRCCS causes of male factor infertility were identified: varicocoele; history of cryptorchidism;
Ospedale San Raffaele, Milan, Italy hypogonadism (primary and secondary); obstructive azoospermia; genetic abnormali-
6
Obstetrics and Gynaecology Department,
ties; other causes (large group including the remnant conditions of known causes); and
IRCCS Ospedale San Raffaele, Milan, Italy
idiopathic infertility. Rates of different male factor infertility causes over the study
Correspondence
period were analyzed. Multivariable logistic regression models tested the likelihood of
Andrea Salonia, University Vita-Salute
San Raffaele, Division of Experimental male factor infertility causes over time. Estimated trends were explored graphically.
Oncology/Unit of Urology, URI-Urological
Results: Of all, varicocoele was found in 615 (37.3%), cryptorchidism in 124 (7.5%), ge-
Research Institute, IRCCS Ospedale San
Raffaele, Via Olgettina 60, 20132 Milan, netic abnormalities in 61 (3.7%), hypogonadism in 165 (10%), obstructive conditions in
Italy.
55 (3.3%), other causes in 129 (7.8%) patients, and idiopathic infertility in 498 (30.3%)
Email: salonia.andrea@hsr.it
patients, respectively. Over time, a reduction in the proportions of cryptorchidism
and varicocoele (all P < 0.001) cases was observed, along with an increase in the pro-
portions of hypogonadism, other causes of MFI and idiopathic cases (all P  ≤  0.01).
Rates of genetic and obstructive cases remained stable. The observed trends were
confirmed at logistic regression models.
Discussion and Conclusions: A decreasing trend in the proportions of varicocoele and
cryptorchidism at first presentation was observed over the last 10 years; conversely,
the proportions of idiopathic cases, hypogonadal patients, and infertile men present-
ing with other male factor infertility causes significantly increased over the same time
frame at a single tertiary-referral academic andrology center.

Giuseppe Fallara and Walter Cazzaniga should be regarded as joint first authors.

© 2020 American Society of Andrology and European Academy of Andrology

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610    
wileyonlinelibrary.com/journal/andr Andrology. 2021;9:610–617.
FALLARA et al.
KEYWORDS
infertility, male factor infertility, semen analysis, varicocoele, hypogonadism, trend
1  |  I NTRO D U C TI O N
According to the World Health Organization (WHO), couple's infer-
tility is defined as the inability of a sexually active couple to achieve
spontaneous pregnancy after 1  year of unprotected intercourse.
[1] Male factor infertility (MFI) is involved in one out of two cases
of couple's infertility, representing the only cause in almost 20% of
cases and contributing jointly with a female infertility factor in the
remaining proportion.[2-6] Therefore, evaluating the fertility status
of the male partner is of utmost importance when dealing with in-
fertile couples, and assessing the prominent cause of male infertility
is an important step toward pregnancy achievement.[4]
Several multifaceted factors have been associated with spermato-
genic abnormalities and subsequent infertility, including genetic, med-
ical, environmental, dietary, and social factors.[7,8] The incidence of
MFI causes differs depending on the study population and the geo-
graphical area.[9] According to the European Urology Association
(EAU) Guidelines, the most commonly reported MFI causes are var-
icocoele, cryptorchidism, hypogonadism, other endocrinopathies (eg,
hypo- or hyper-thyroidism, hyperprolactinemia), immunologic factors
(eg, antisperm antibody), obstruction of male genital tract (eg, mu-
tations in the cystic fibrosis transmembrane conductance regulator
(CFTR) gene causing azoospermia; either congenital or acquired ab-
normalities of seminal vesicle, epididymis or ejaculatory duct), genetic
abnormalities (ie, mutations in the cystic fibrosis transmembrane con-
ductance regulator (CFTR) gene; Y-chromosome microdeletion; and,
karyotype alterations), drugs (eg, chemotherapies; anabolic drugs) or
surgery (eg, prostate surgery), and idiopathic infertility.[4]
While a number of reports documented impoverishment of the
quality of sperm parameters [10] and MFI incidence in different
countries,[4] few attempts have been undertaken to assess temporal
patterns of MFI causes. Accurate knowledge on the rates of infertil-
ity causes and their trends over time is essential for clinicians dealing
with infertile couples, as well as for national health agencies.
We sought to assess the rates of MFI causes in men presenting
with primary couples' infertility at a single referral outpatient aca-
demic andrology center and to estimate temporal trends over the
last 10 years in order to provide a real-life picture of the changing
patterns in clinical practice.
2  |  M ATE R I A L A N D M E TH O DS
2.1  |  Study population
Data from 1647 consecutive patients seeking medical help for pri-
mary couple's infertility associated with pure MFI at a single tertiary-
referral academic center between January 2008 and December
2018 were analyzed.
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      611
All patients were comprehensively assessed with a detailed med-
ical history, including data on health-significant comorbidities, scored
with the Charlson Comorbidity Index (CCI) using the International
Classification of Diseases, 10th revision, Clinical Modification (ICD-
10-CM).[11] Measured body mass index (BMI), defined as weight in
kilograms by height in square meters (kg/m2), was obtained for each
participant. Testis volume was assessed using a Prader orchidome-
ter, calculating the mean value between the two sides. Evidence of
varicocoele was clinically assessed in every participant according to
current guidelines.[4]
All patients underwent at least two semen analyses and sperm
parameters were assessed based on 1999 WHO reference criteria
for patients until 2010 and based on 2010 WHO reference criteria
for patents after 2010. Overall, at post hoc analyses, oligozoosper-
mia was defined as having a sperm concentration  <  15  million/ml;
asthenozoospermia with a sperm progressive motility  <  32%, and
theratozoospermia with  <  4% of normal morphology spermatozoa
in semen.[12]
Patients were further stratified into four groups, as follows: eu-
gonadal [normal total testosterone (tT) (≥10.5  nmol/l) and normal
LH (≤9.4 mUI/ml)]; secondary hypogonadism [low tT (≤10.5 nmol/l)
and low/normal LH (≤9.4  mUI/ml)]; primary hypogonadism [low tT
(≤10.5  nmol/l) and elevated LH (>9.4  mUI/ml)]; and, compensated
hypogonadism [normal tT (≥10.5 nmol/l) and elevated LH (>9.4 mUI/
ml)].[13,14]
Data collection followed the principles outlined in the
Declaration of Helsinki. After obtaining written individual patient's
consent agreeing to use of their own anonymized details for future
studies, clinical data from all patients were retrieved using a dedi-
cated case report form, according to an institutional protocol. The
study was approved by the IRCCS San Raffaele Hospital Ethical
Committee (Prot. 2014—Pazienti Ambulatoriali).
2.2  |  Outcomes
The outcome of the study was to evaluate the changing rates of
MFI causes in men diagnosed with primary infertility over the study
period at our center. In order to maintain adequate homogeneity in
terms of possible MFI causes definition and classification, we relied
on the series of most common causes according to the current EAU
Guidelines on male sexual and reproductive health.[4] Accordingly, the
recorded causes were grouped with the following criteria and hierar-
chy in the case of multiple contemporary causes: “obstructive,” in case
of obstructive azoospermia, whatever the underlying cause was [15];
“genetic,” if karyotype abnormalities and/or Y-microdeletion and/or
CFTR gene mutations were present [16]; history of “cryptorchidism” or
ascending testis at presentation [17]; “hypogonadism,” if testosterone
was lower than 10.5 nmol/l in the case of both primary or secondary
612      | FALLARA et al.

TA B L E 1  Descriptive statistics of the whole cohort of patients

hypogonadism [14]; “others,” when other known causes were potential
(n, 1647)
responsible factors (eg, hormonal causes, other than hypogonadism;
N, 1647 cancer and cancer therapies; infectious conditions; immunological dis-
Age at presentation, years 37 (33-41) orders; drugs, recreational drugs and illicit substances; and, erectile or
BMI, kg/cm 2
25 0.5 (23.5-27.5) ejaculatory dysfunction); “varicocoele,” in the case of varicocoele and
Smoking status no other more probable causes of infertility [18]; finally, “idiopathic” if

No 893 (54.2) no specific causes could have been found.[4]

Ex-smoker 200 (12.1)

Yes 554 (33.6)
2.3  |  Statistical analyses
CCI
0 1559 (94.7)
Statistical analyses as well as reporting and interpretation of the
1 51 (3.1)
results were conducted according to established guidelines and
+2 37 (2.2) consisted of four steps.[19] First, to describe patient characteristics
Testis volume, mL 4.5 (3.4-5.8) at presentation we reported patients baseline characteristics along
FSH, mIU/ml 5.7 (3.4-11.8) with their hormonal and semen profiles, using counts and propor-
LH, mUI/ml 4.2 (2.9-6.1) tions for categorical variables or medians and interquartile ranges
a
Total testosterone, mg/dl   4.2 (3.5-5.1) (IQR) for continuous variables. ANOVA and multiple-way Chi Square
Primary hypogonadism 29 (1.8) tests were used for multiple groups comparison. Second, to describe
Secondary hypogonadism 185 (11.2) the observed trends of the above-mentioned MFI causes during the

Compensated hypogonadism 69 (4.2)

study period, we reported and graphically explored the rates of di-
agnosis of each cause per year. Third, we used multivariable logistic
Ejaculate volume, ml 3 (2-4)
regression analysis to test the hypothesis that year of diagnosis was
Sperm concentration, millions/ml 10 (0.8-36)
significantly associated with MFI causes, after adjusting for age at
Sperm progressive motility, % 16 (0-33.5)
diagnosis, BMI, CCI, and smoking status. Covariates were chosen
Sperm normal morphology, % 2 (0-7)
among available factors supposed to be associated with MFI causes.
Azoospermia
Finally, in order to confirm the observed trends of MFI causes over
No 1329 (80.7) time, expected rates of MFI causes according to the regression mod-
NOA 262 (15.9) els were displayed by use of lowess stacked-curves.
OA 55 (3.3) Statistical analyses were performed using the RStudio graphical in-
Oligozoospermiab  terface v.0.98 for R software environment v.3.0.2 (http://www.r-proje​
No 708 (43) ct.org). All tests were two-sided with a significance level set at P < 0.05.
Yes 939 (57)
Theratozoospermiac 
No 521 (31.6)
3  |  R E S U LT S
Yes 1126 (68.4)
d
Table  1 details patients characteristics at diagnosis. According to
Asthenozoospermia  
MFI cause at presentation during the whole study period, of 1647,
No 431 (26.2)
615 (37.3%) patients had varicocoele, 165 (10%) had criteria sugges-
Yes 1216 (73.8)
tive for hypogonadism, 124 (7.5%) had history of cryptorchidism, 61
Note: Median (IQR) is used for continuous variable, number (proportion) (3.7%) had genetic abnormalities, 55 (3.3%) had obstructive causes,
for categorical variables 129 (8.6%) presented with other causes, and 498 (30.3%) were idi-
Abbreviations: BMI, Body Mass Index; CCI, Charlson Comorbidity
opathic in nature (Table 2).
Index; FSH, Follicle Stimulating Hormone; IQR, Interquartile range;
NOA, Non-Obstructive Azoospermia; OA, Obstructive Azoospermia. Rates of MFI causes throughout the 10-year period are de-
a
Hypogonadism was defined as: eugonadal (total Testosterone picted in Table  3. Figure  1 graphically represents trends of pro-
(tT) ≥ 10.5 nmol/l and LH ≤ 9.4 mUI/ml); secondary hypogonadism portions of MFI causes at presentation. Over time, proportions of
(tT ≤ 10.5 nmol/l and LH ≤ 9.4 mUI/ml); primary hypogonadism cryptorchidism and varicocoele cases at presentation decreased
(tT ≤ 10.5 nmol/l and LH > 9.4 mUI/ml); and, compensated
(all P  <  0.001). Conversely, the proportions of hypogonadal pa-
hypogonadism (tT ≥ 10.5 nmol/l and elevated LH > 9.4 mUI/ml)
b tients, of men with other causes of MFI and of idiopathic cases
Oligozoospermia was defined as a spermatozoa count ≤ 15 millions/
mL. Azoospermia cases are included in oligozoospermia. significantly increased (all P  ≤  0.04). Genetic cases and men with
c
Theratozoospermia was defined as a normal morphology < 4%. obstructive disorders showed stable proportions during the study
d
Asthenozoospermia was defined as a progressive motility < 32%. period (Table 3).
FALLARA et al. |
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TA B L E 2  Patient characteristics according to MFI causes

Cryptorchidism Genetic Hypogonadism Idiopathic Obstructive Others Varicocoele
(n = 124) (n = 61) (n = 165) (n = 498) (n = 55) (n = 129) (n = 615) p-value
Age at presentation, 37 (34-40) 38 (32-40) 38 (34-41) 37 (33-41) 39 (34-42) 38 (33-41) 36 (33-40) <0.001
years

BMI, kg/m2 25.5 (23.5-27.2) 25.4 (23-27.1) 26.8 (24.9-29.8) 25 (23.4-26.9) 24.6 (23.1-26.3) 24.8 (23.4-26.7) 24.4 (22.8-26.3) <0.001

CCI

0 118 (95.2) 56 (91.8) 154 (93.3) 468 (94) 52 (94.5) 123 (95.3) 588 (95.6) 0.9

1 1 (0.8) 4 (6.6) 8 (4.8) 17 (3.4) 2 (3.6) 3 (2.3) 16 (2.6)

+2 5 (4) 1 (1.6) 3 (1.8) 13 (2.6) 1 (1.8) 3 (2.3) 11 (1.8)

Smoke

No 69 (55.6) 32 (52.5) 96 (58.2) 251 (50.4) 33 (60) 71 (55) 341 (55.4) 0.2

Ex-smoker 18 (14.5) 6 (9.8) 25 (15.2) 71 (14.3) 3 (5.5) 16 (12.4) 61 (9.9)

Yes 37 (29.8) 23 (37.7) 44 (26.7) 176 (35.3) 19 (34.5) 42 (32.6) 213 (34.6)

Testis volume, ml 12 (10-18) 11 (5.2-13.8) 15 (11-20) 18 (14-23) 18 (12-20) 15 (12-20) 15 (12-20) <0.001

FSH, mIU/ml 12.1 (5.9-19.7) 15.4 (6-23.9) 6 (3.4-13.3) 5.1 (3.1-9.1) 4.5 (3.1-6.4) 7.1 (3.7-12.1) 5.2 (3.2-9.4) <0.001

LH, mUI/ml 5.5 (3.8-8.1) 7.6 (4.7-12.7) 4.0 (2.5-6.1) 4.0 (2.8-5.6) 3.3 (2.5-4.2) 4.2 (3.2-6.3) 4.2 (2.9-5.7) 0.09

Total testosterone, 4.2 (3.5-5.1) 3.9 (2.8-5.6) 2.6 (2.2-2.8) 5.2 (4-6.2) 4.5 (3.8-5.3) 4.9 (3.7-6) 5 (4.1-6.1) <0.001
mg/dl

Ejaculate volume, ml 3 (2-4) 3 (2-4) 3 (2-4) 3 (2-4) 2 (1-3) 3 (2-4) 3 (2-4) 0.5

Sperm concentration, 0.3 (0-12.2) 0 (0-0.9) 4.8 (0-22) 20 (4-48.5) 0 (0-0) 8 (0.5-32.8) 15 (3-39.2) <0.001
millions/mL

Sperm progressive 6 (0-29) 1 (0-2) 9 (0-27) 25 (8-41) – 18 (2-31) 20 (5-35) 0.03

motility, %

Sperm normal 2 (0-2) 1 (0-4) 1 (0-6) 2 (1-8) – 2 (0-10) 2 (0-9) 0.003

morphology, %

Azoospermia

No 69 (55.6) 20 (32.8) 121 (73.3) 458 (92) 0 (0) 106 (82.2) 555 (90.2) <0.001

NOA 54 (43.5) 41 (67.2) 44 (26.7) 40 (8) 0 (0) 23 (17.8) 60 (9.8)

OA 0 (0) 0 (0) 0 (0) 0 (0) 55 (100) 0 (0) 0 (0)

Oligozoospermiaa 

No 26 (21) 3 (4.9) 51 (30.9) 275 (55.2) – 49 (38) 304 (49.4) <0.001

Yes 98 (79) 58 (95.1) 114 (69.1) 223 (44.8) – 80 (62) 311 (50.6)

Theratozoospermiab 

No 25 (20.2) 7 (11.5) 46 (27.9) 184 (36.9) – 43 (33.3) 216 (35.1) <0.001

Yes 99 (79.8) 54 (88.5) 119 (72.1) 314 (63.1) – 86 (66.7) 399 (64.9)

Asthenozoospermiac 

No 20 (16.1) 2 (3.3) 27 (16.4) 177 (35.5) – 29 (22.5) 176 (28.6) 0.04

Yes 104 (83.9) 59 (96.7) 138 (83.6) 321 (64.5) – 100 (77.5) 439 (71.4)

Note: Median (IQR) is used for continuous variable, number (proportion) for categorical variables
Abbreviations: BMI, Body Mass Index; CCI, Charlson Comorbidity Index; FSH, Follicle Stimulating Hormone; IQR, Interquartile range; NOA, Non-Obstructive
Azoospermia; OA, Obstructive Azoospermia.
a
Oligozoospermia was defined as a spermatozoa count ≤ 15 millions/mL. Azoospermia cases are included in oligozoospermia.
b
Theratozoospermia was defined as a normal morphology < 4%
c
Asthenozoospermia was defined as a progressive motility < 32%

Patients seeking medical help over the last 10  years were less
likely to present with varicocoele, history of cryptorchidism, or ob-
structive causes (all P  ≤  0.03), after adjusting for age at diagnosis,
CCI, BMI, and smoking status (Table 4). Conversely, they had higher
probability of presenting with hypogonadism, other causes of infer-
tility or idiopathic infertility (all P ≤ 0.03), over the same time frame
(Table 4). Figure 2 represents the expected rates of MFI causes at
first presentation over the whole period of assessment, according
to the regression models; the figure graphically displays a reduction
in proportions of cryptorchidism, obstructive conditions, and var-
icocoele cases, but an increase in rates of other causes of MFI, idio-
pathic MFI, and hypogonadism cases.
4  |  D I S C U S S I O N
Our findings provide a realistic picture of the real-life scenario in
a tertiary-referral andrology center dealing with reproductive
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614      FALLARA et al.

TA B L E 3  Proportion (95 % confidence interval) of MFI causes during the study time frame divided into biennial periods

2008-2010 2010-2012 2012-2014 2014-2016 2016-2018 p-value

Cryptorchidism (n, 124) 11% (5-16) 8% (3-14) 7% (1-13) 11% (5-17) 2% (0-8) 0.001
Genetic (n, 61) 3% (0-8) 4% (0-10) 4% (0-10) 6% (0-12) 2% (0-8) 0.3
Hypogonadism (n, 165) 9% (3-14) 8% (3-14) 11% (5-17) 1% (5-16) 12% (7-17) 0.04
Idiopathic infertility (n, 498) 26% (21-31) 27% (21-33) 33% (27-39) 32% (27-38) 33% (28-39) 0.003
Obstructive (n, 55) 6% (0-11) 3% (0-9) 4% (0-10) 2% (0-8) 2% (0-7) 0.07
Other (n, 129) 8% (2-13) 3% (0-9) 8% (2-14) 6% (0-12) 13% (8-18) <0.001
Varicocoele (n, 615) 39% (34-45) 46% (41-52) 33% (27-39) 32% (27-38) 36% (31-41) <0.001

Abbreviation: MFI, male factor infertility.

help for primary couple's infertility were relatively old,[20,21] in line

F I G U R E 1  Trends in rates of male infertility causes at first
presentation between 2008 and 2018 [Colour figure can be viewed
at wileyonlinelibrary.com]
medicine, with relevant changes over time in terms of causes of MFI
at first presentation. Indeed, during the last decade, a significant
decreasing was observed in the proportion of men presenting with
a history of cryptorchidism or varicocoele, along with an increased
proportion of men with hypogonadism (as for a widely accepted
definition [13]), other causes of MFI and idiopathic infertility at first
presentation. Noteworthy, we confirmed that men seeking medical
with the evidences of increasing age at presentation in infertile cou-
ples, and that they had a relevant burden of sperm abnormalities.[22]
This latter finding was further outlined by a trend toward a worsen-
ing of sperm parameters over the entire study period (Table S1) and
it is in line with previous published studies.[10] Taken together, our
results confirm their validity as a reliable picture of a tertiary-referral
andrology center committed today in the field of reproductive medi-
cine, in addition to the increasing complexity of cases at their first
presentation.
Overall, prevalence and incidence of MFI have increased world-
wide [9]; in this context, despite a detailed description of risk fac-
tors or causes of pure MFI, their relative trends have been scantly
detailed.[21] Indeed, most reports mainly described rates of oligo/
astheno/teratozoospermic men rather than comprehensively char-
acterizing patients according to the specific MFI cause at presenta-
tion. Notably, our current findings depicted a significant decreasing
trend in the proportions of some of the most common causes (eg,
varicocoele and history of cryptorchidism), with increase propor-
tions of idiopathic cases, hypogonadal cases and MFI associated
with other causes (eg, endocrine dysregulation, drugs use, recre-
ational drugs intake, etc).

TA B L E 4  Multivariate logistic regression models assessing the risk of each MFI diagnosis according to the year of diagnosis after
adjusting for age at diagnosis, CCI, BMI, and smoke

Varicocoele Cryptorchidism Genetic

OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value

Year of diagnosis 0.95 (0.92-0.98) 0.002 0.87 (0.81-0.93) <0.001 1.00 (0.92-1.09) 0.9
Age at diagnosis 0.97 (0.96-0.99) <0.001 1.00 (0.97-1.03) 0.8 0.99 (0.96-1.03) 0.8
CCI
0 (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref)
1 0.85 (0.45-1.54) 0.6 0.22 (0.01-1.03) 0.1 2.38 (0.69-6.23) 0.1
+2 0.80 (0.37-1.63) 0.6 1.91 (0.63-4.71) 0.2 0.83 (0.05-4.01) 0.9
BMI 0.92 (0.89-0.95) <0.001 1.00 (0.95-1.06) 0.9 1.01 (0.93-1.08) 0.8
Smoking
No (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref)
Ex-smoker 0.83 (0.58-1.17) 0.3 1.83 (1.00-3.23) 0.04 0.83 (0.3-1.94) 0.7
Smoking 1.10 (0.88-1.39) 0.4 0.98 (0.64-1.49) 0.9 1.14 (0.64-1.99) 0.6

Abbreviations: BMI, Body Mass Index; CCI, Charlson Comorbidity Index.

FALLARA et al. |
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Previous studies on white-Europeans depicted a prevalence
of varicocoele in primary infertile patients ranging between 25%
and 35% of the cases, but no temporal trend had been analyzed.
[23,24] Here, we detailed a reduction in the proportion of varico-
coele cases at presentation, which was also the case for cryptor-
chidism. This latter condition might be explained with finding from
a population-based study which described an increased incidence
of early diagnosis of undescended testis over the last decades
in some European regions (eg, UK, Sweden, Norway, Denmark),
mainly due to screening programs and a greater attention payed
by pediatricians and parents to this condition.[25] As a conse-
quence, earlier surgical repair has been implemented and this
might be one of the reasons for reduced rates of sperm abnormal-
ities and MFI associated with undescended testis.[26] Some not
unique evidences have been published suggesting a positive out-
come after surgical correction of either unilateral or bilateral con-
genital cryptorchidism below 1 year of age, and in some reports,
almost equal paternity rates compared to sane controls have been
found in case of timely surgical correction of unilateral cryptor-
chidism.[27-29] Conversely, increased rates of male hypogonadism
represent a relevant problem all over the world, both in general
population and in infertile men, where it accounts for 10%–20%
of all MFI causes [14]; we confirm previous findings of such an in-
creasing trend of hypogonadal cases also in the subset of primary
infertile patients. Here, we observed a stable 4% rate of genetic
abnormalities in infertile patients at diagnosis, which is in line with
the reported 5%–10% prevalence from other European centers.
[16,30] Of note, relevant attention has been given to study the
genetic causes of MFI over the last decades; thereof, a large panel
of karyotype and genetic testing is now available, and updated sci-
entific guidelines are gradually adapting to different investigation
thresholds.[30,31] Obstructive causes account for more than 5%
of all infertile cases, with increasing figures in azoospermic cases.
[32] No evidence exists in literature on diagnostic trends for this
specific condition in the last decades; in our cohort, a slight but not
significant decrease in the proportion of obstructive azoospermic
cases was observed over time. Finally, and of paramount clinical
importance, idiopathic causes account for up to 60% of all MFI
causes in the literature [33]; here, we confirm this dramatic trend,
notwithstanding comparisons with previous published studies are
almost impossible since heterogeneity in terms of geographic and
ethnic distributions of studied cohorts might lead to relevant dis-
crepancies among final diagnoses. Anyhow, such a high proportion
of idiopathic cases highlights the urgent need for more efforts to-
ward a deeper understanding of MFI causes and their pathobiol-
ogy role in terms of couple's infertility.
This work has several strengths. First, it provides a novel
comprehensive investigation of trends of MFI causes over the
last 10 years. Moreover, it depicts a realistic picture of historical
changes occurred in a relatively short time frame in the every-day
clinical practice at a single tertiary-referral andrology center deal-
ing with reproductive medicine with large generalist case load that
might resemble population trends. Likewise, a relatively large ho-
mogenous cohort of single-ethnicity patients, the granular data
on semen analyses, serum hormonal tests, and MFI causes add
further valuable evidence to the existing literature. Of relevance,
a standardized internal protocol has been applied throughout the
study period in terms of diagnostic work-up for each patient, thus
enough to minimize the possible intra diagnostic variability in the
sample.
This study is certainly not devoid of limitations. First, giving its
retrospective nature we acknowledge the possibility of some se-
lection and information bias. To reduce selection bias, we have at-
tempted to be as much inclusive as possible, without applying any
strict exclusion criteria. Moreover, the risk of outcomes misclassifi-
cation is intrinsic to the retrospective design of the study itself and
difficult to address; indeed, no univocal guidelines on MFI causes
diagnosis exist and, in some cases, multiple causes coexisted in a

Idiopathic Obstructive Hypogonadism Other

OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value

1.06 (1.02-1.09) 0.03 0.9 (0.81-0.98) 0.03 1.06 (1.01-1.12) 0.04 1.11 (1.05-1.18) <0.001
1.02 (1.00-1.03) 0.3 1.04 (1.00-1.08) 0.03 1.02 (0.99-1.04 0.2 1.01 (0.98-1.03) 0.7

1.00 (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref)

1.18 (0.63-2.13) 0.6 1.43 (0.60-3.02) 0.9 1.43 (0.60-3.02) 0.4 0.76 (0.18-2.14) 0.7
1.09 (0.51-2.22) 0.8 0.79 (0.19-2.30) 0.5 0.79 (0.19-2.30) 0.7 1.15 (0.27-3.32) 0.8
1.00 (0.97-1.03) 0.9 0.95 (0.87-1.03) 0.2 1.18 (1.13-1.23) <0.001 1.01 (0.96-1.06) 0.7

1.00 (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref)

1.22 (0.87-1.71) 0.2 0.54 (0.13-1.58) 0.3 0.93 (0.55-1.52) 0.7 0.80 (0.43-1.41) 0.5
1.04 (0.81-1.32) 0.8 0.89 (0.47-1.61) 0.7 0.70 (0.47-1.03) 0.08 1.01 (0.67-1.52) 0.9
 |
616      FALLARA et al.
F I G U R E 2  Expected trends of MFI causes according to the
logistic multivariable models [Colour figure can be viewed at
wileyonlinelibrary.com]
patient, thus making somehow challenging and arbitrary to define
their priority from medical reports. A further selection bias might be
intrinsic to the tertiary-referral and academic nature of our center,
which may explain the reduction of patients presenting with rela-
tively simple causes and, in contrast, higher rates of more complex
infertility conditions. If this would be the case, still our data depict
the real-life scenario at a large case load andrology center over the
last 10 years. Third, although on the one hand having homogeneous
data from white-Caucasian patients only may represent a further
strength of the analyses, on the other different geographical areas
and ethnicity groups might have depicted different patterns over the
same time frame. Fourth, throughout the last 10-year frame, envi-
ronmental, biological, and social factors might have changed, with a
relevant pathobiological impact on MFI causes and the subsequent
fertility rates. Nonetheless, given the paucity of data on temporal
patterns of MFI causes over the last years, our data add further evi-
dences to the existing literature and stimulate further epidemiologi-
cal studies on the relevance of the male factor pathobiology in terms
of couple's infertility.
5  |   CO N C LU S I O N S
A decreasing trend in the proportions of varicocoele and cryptor-
chidism cases at first presentation was observed for male infertility
over the last decade at a single tertiary-referral andrology center
with a large case load of primary infertile couples. Conversely, the
proportions of hypogonadal cases, cases of otherwise origin and
idiopathic cases significantly increased over the same period of
time. As a whole, current findings further stress the importance
of a comprehensive diagnostic work-up at first presentation of
infertile couples with pure male factor infertility, with temporal
changes which may reliably mirror overall medical, environmen-
tal, and social factors. Larger studies with different geographical
and ethnical realities are compulsory to externally validate our
observations.
C O N FL I C T O F I N T E R E S T
The authors have no conflict of interest to disclose.
AU T H O R C O N T R I B U T I O N S
AS, WC, and GF designed the study, analyzed the data, and inter-
preted the results. WC, LB, EP, FB, LC, NS, EV, and CA collected the
data. AS, WC, and GF wrote the manuscript. All authors critically
reviewed and approved the final version of the manuscript.
ORCID
Giuseppe Fallara  https://orcid.org/0000-0001-7872-2650
Paolo Capogrosso  https://orcid.org/0000-0003-2347-9504
Federico Belladelli  https://orcid.org/0000-0002-2165-659X
Eugenio Ventimiglia  https://orcid.org/0000-0003-3654-1629
Andrea Salonia  https://orcid.org/0000-0002-0595-7165
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S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found online in the
Supporting Information section.
How to cite this article: Fallara G, Cazzaniga W, Boeri L, et al.
Male factor infertility trends throughout the last 10 years:
Report from a tertiary-referral academic andrology centre.
Andrology. 2021;9:610–617. https://doi.org/10.1111/andr.12947