This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. 
© 2021 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada. 

Key Words Competing Interests Article Information

Type 1 diabetes, male infertility, clinical 
predictors

Dr Hehemann is a consultant for Boston 
Scientific Corporation. The remaining authors 
declare no competing interests.

Received on December 22, 2020 
Accepted on March 1, 2021

Soc Int Urol J.2021;2(3):139–143

DOI: https://doi 10.48083/ VVMV5977

Does Type 1 Diabetes Affect Male  
Infertility: Type 1 Diabetes Exchange  
Registry-Based Analysis

Omer A. Raheem,1 Marah C. Hehemann,2 Marc J. Rogers,3 Judy N. Fustok,1  
Irl B. Hirsch,4 Thomas J. Walsh2

1 Department of Urology, Tulane University, New Orleans, United States 2 Department of Urology, University of Washington, Seattle, United States 3 Department of 
Urology, Medical University of South Carolina, United States 4 Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States

Abstract

Introduction The prevalence of type 1 diabetes (T1D) has been increasing over the last few decades and is commonly 
believed to negatively impact male fertility. We aimed to estimate the prevalence of infertility among men with T1D 
and to characterize potential clinical predictors for male infertility among men with T1D.

Methods We used data collected from the T1D Exchange Registry from 2012 to 2017. Men with T1D completed 
an infertility questionnaire indicating whether they had ever had problems conceiving a child or had ever received 
abnormal results from infertility testing. Collected data included age at questionnaire, age at diagnosis of T1D, 
duration of T1D, race/ethnicity, insurance status, education level, annual household income, hemoglobin A1c 
(HbA1c), low density lipoprotein (LDL), diabetic retinopathy, micro/macroalbuminuria, and renal failure.

Results The survey was completed by 2171 registry members, 33 (1.5%) of whom reported male infertility. Mean 
age at questionnaire was 38 and 56 years in the fertile and infertile groups, respectively (P < 0.001). There was no 
statistically significant difference in the mean age at T1D diagnosis (16 and 27 years), mean duration of T1D at 
questionnaire (22 and 30 years), white non-Hispanic ethnicity (1906/2138, 89% versus 30/33, 91%), private insurance 
(1509/2138, 79% versus 30/33, 91%), and annual household income in US dollars ≥ $100 000 (757/2138, 45% versus 
16/33, 55%) in the fertile and infertile men, respectively. On multivariate analysis, for each year of advancing age, men 
were 5% more likely to experience infertility. Age at questionnaire was the only significant predictor of infertility (OR 
1.05; 95%CI 1.03 to 1.08). Age at T1D diagnosis (OR 1.01; 95%CI 0.99 to 1.04), duration of T1D (OR 0.99; 95%CI 0.96 to 
1.01), mean HbA1C (OR 1.03; 95%CI 0.77 to 1.37), diabetic retinopathy (OR 1.04; 95%CI 0.50 to 2.15), and mean LDL 
(OR 1.01; 95%CI 0.99 to 1.02) failed to independently predict infertility; however, presence of renal failure (OR 3.38; 
95%CI 0.94 to 12.13) and micro/macroalbuminuria (OR 1.27; 95%CI 0.42 to 3.82) trended toward increased odds of 
infertility.

Conclusions This study highlights the prevalence of male infertility among men with T1D. Beyond age, there were 
no independent clinical predictors for male infertility among men with T1D; however, men with clinical evidence of 
diabetes-associated renal compromise trended toward greater odds of infertility. Further studies of fertility in this 
growing, at-risk population are warranted.

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TABLE 1.

Patient demographics and characteristics

Variable
Fertile

N = 2138
n (%) 

Infertile 
N = 33
n (%)

Age at questionnaire years (mean)a

18–25
26–34
35–49

≥ 50

38
872 (41)
239 (11)
407 (19)
620 (29) 

56
0
0

13 (39)
20 (61)

Age at diagnosis years (mean)
<6

6–12
13–17
18–25
26–49

≥ 50

16
340 (16)
784 (37)
345 (16)
231 (11)
396 (19)
42 (2)

27
4 (12)
6 (18)
4 (12)
5 (15)
8 (24)
6 (18)

Duration of T1D at questionnaire
years (mean)

1–9
10–19
20–49

≥ 50

22

400 (19)
818 (38)
817 (38)
103 (5)

30

2 (6)
7 (21)

23 (70)
1 (3)

Race/Ethnicity
White non-Hispanic
Black non-Hispanic
Hispanic or Latino

Others

1906 (89)
46 (2)
118 (6)
68 (3)

30 (91)
1 (3)
2 (6)

0

Insurance status
Private insurance

Other insurance
No insurance 

1509 (79)
381 (20)
11 (<1)

30 (91)
3 (9)

0

Education level
<High school

High school/associates
Bachelors

Masters
Professional/doctorate

95 (5)
981 (46)
660 (31)
239 (11)
136 (6)

0
10 (30)
11 (33)
6 (18)
6 (18)

Annual household income (US$)
< 35 000

35 000–< 50 000
50 000–< 75 000

75 000–< 100 000
≥ 100 000

285 (17)
133 (8)

232 (14)
263 (16)
757 (45)

3 (10)
2 (7)
3 (10)
5 (17)

16 (55)

a P < 0.001

Introduction

The prevalence of type 1 diabetes (T1D) has been 
increasing worldwide and in the United States over last 
few decades and commonly manifests during childhood. 
T1D is an autoimmune destruction of the pancreatic 
beta-cells that ultimately leads to failure of insulin 
production. Several important risk factors for T1D have 
been identified and include obesity, family history, and 
genetic polymorphisms[1,2]. More importantly, T1D 
is associated with an increased risk of cardiovascular 
disease and mortality, and clinical prognosis worsens if 
T1D is left untreated[3].

It has been suggested that male infertility is not a unique 
disease of the reproductive axis, but rather a clinical 
marker underpinning overall health and well-being in 
men[4,5]. While research has focused on the relationship 
between metabolic syndrome, obesity, dyslipidemia, 
hypertension, and insulin resistance or genitourinary 
malignancies on male infertility, there is paucity of 
contemporary literature specifically addressing the 
detrimental effects of T1D on male fertility[6,7].

In this study, we sought to characterize the prevalence 
of infertility among men with T1D. We hypothesized 
that the rate of infertility among men with T1D would 
be higher than rate reported in the general population. 
Additionally, we sought to identify clinical predictors of 
infertility among men with T1D.

Materials and Methods
Study population and design
The study was conducted using the large dataset 
collected from the T1D Exchange Registry[8]. The 
protocol was approved by the University of Washington 
Institutional Review Board, and study participants 
provided written informed consent. The T1D Exchange 
Registry provides demographic and clinical information 
on individuals diagnosed with T1D in the United States, 
offering a broad representation of pediatric and adult 
patients with T1D. Data are collected for the registry 
database at enrollment and then once a year. Data are 
obtained through (1) completion of a questionnaire 
by the participant or parent of the participant and (2) 
retrieval of information collected from the medical 
records[8].

Fertility was determined using 2 questions on male 
infertility in the T1D Exchange Registry questionnaire: 
(1) Have you ever had problems conceiving a child? 
Yes/No (2) Have you ever received infertility testing? 
Yes/No; if yes, (2a) were the test results normal? Yes/
No (Appendix 1). Men were considered infertile if they 
indicated they had previously had problems conceiving 
a child and/or if they had abnormal test results on 
infertility testing. Otherwise, men were assigned to the 

140 SIUJ  •  Volume 2, Number 3  •  May 2021 SIUJ.ORG

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fertile group.

Collected data included age at questionnaire, age 
at diagnosis of T1D, duration of T1D, race/ethnicity, 
insurance status, education level, annual household 
income, hemoglobin A1c (H bA1c), low densit y 
lipoprotein (LDL), diabetic retinopat hy, micro/
macroalbuminuria, and renal failure. Linear regression 
multivariate models were performed to assess the 
clinical predictors of T1D patients associated with male 
infertility.

We sought to determine the prevalence of infertility 
in males with T1D. Secondarily, we sought to identify 
the clinical predictors of infertility among T1D men.

Statistical analysis
We used the Mann-Whitney U test and chi-square test 
for continuous and categorical variables, comparing 
the fertile and infertile groups. Multivariable analysis 
was also performed to identify these clinical factors 
associated with male fertility. Statistical significance 
was defined by P-value < 0.05. All data analysis was 
performed using statistical software R version 3.3.2.

Results
In this study, a total of 2171 out 3955 men completed the 
infertility portion of the year 5 questionnaire within the 
T1D Exchange Registry from 2012 to 2017. This database 
includes 18 743 participants from 79 clinic sites. T1D 
Exchange Clinic Network is coordinated by the Jaeb 
Center for Health Research, a nonprofit clinical research 
coordinating center in Tampa, Florida.

Thirty-three men (1.5%) reported male infertility. 
Mean age at questionnaire was 38 and 56 years in the 
fertile and infertile groups, respectively (P < 0.001). 
There was no statistically significant difference in the 
mean age at T1D diagnosis (16 versus 27 years), mean 
duration of T1D at questionnaire (22 versus 30 years), 
white non-Hispanic ethnicity (1906/2138, 89% versus 
30/33, 91%), private insurance (1509/2138, 79% versus 
30/33, 91%), and annual household income in US dollars 
≥ $100 000 (757/2138, 45% versus 16/33, 55%) in the 
fertile and infertile men, respectively (Table 1).

On multivariate analysis, for each year of advancing 
age men were 5% more likely to experience infertility. 
Age at questionnaire was the only significant predictor 
of infertility (OR 1.05; 95%CI 1.03 to 1.08). Age at T1D 

TABLE 2.

Multivariate analysis for clinical predictors of T1D patients associated with male infertility

Variables/Predictors 
Fertile
N (%)

Infertile
N (%)

Unadjusted OR (95% CI) Adjusted OR (95% CI)

Age at diagnosis, years (mean) 16 27
1.05

(1.03–1.07)
1.01

(0.99–1.04)

Duration of T1D at questionnaire, years (mean) 22 30
1.04

(1.01–1.06)
0.99

(0.96–1.01)

Hemoglobin A1c (HbA1c) mg/dL (mean) 8.0 7.7
0.84

(0.64–1.10)
1.03

(0.77–1.37)

Diabetic retinopathy 566 (28) 14 (42)
0.54

(0.27–1.08)
1.04

(0.50–2.15)

Renal status
Renal failure

Micro/macroalbuminuria
No albuminuria

32 (2)
156 (8)

1887 (91)

3 (10)
4 (13)

23 (77)

7.69 (2.20–26.93)
2.10 (0.72–6.16)

Ref

3.38 (0.94–12.13)
1.27 (0.42–3.82)

Ref

Low density lipoprotein level, mg/dL (mean) 90.5 88.4 1.00 (0.98–1.01)
1.01 (0.99–1.02)

aAdjusted for age at questionnaire

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Does Type 1 Diabetes Affect Male Infertility: Type 1 Diabetes Exchange Registry-Based Analysis

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diagnosis (OR 1.01; 95%CI 0.99 to 1.04), duration of 
T1D (OR 0.99; 95%CI 0.96 to 1.01), mean HbA1C (OR 
1.03; 95%CI 0.77 to 1.37), diabetic retinopathy (OR 1.04; 
95%CI 0.50 to 2.15), and mean LDL (OR 1.01; 95%CI 
0.99 to 1.02) failed to independently predict infertility; 
however, presence of renal failure (OR 3.38; 95%CI 0.94 
to 12.13) and micro/macroalbuminuria (OR 1.27; 95%CI 
0.42 to 3.82) trended toward increased odds of infertility 
(Table 2).

Discussion
Recent studies have linked diabetes mellitus (DM) 
(type 1 or 2) and infertility with an increased risk of 
developing DM among infertile men which can reach as 
high as 30%[9]. This association has been reproduced in 
a large prospective Danish in vitro fertilization registry 
by Glazer et al. of 39 516 men who had undergone 
fertility treatment with their female partner with a 
median follow-up time of 5.6 years. This study found 
651 (1.6%) cases of type 1 or 2 DM among men with 
infertility (eg, oligospermia, azoospermia) with the risk 
being related to the severity of the underlying fertility 
problem[10]. In our study, 33 men out of 2171 (1.5%) with 
T1D reported infertility, which supports the findings of 
Glazer et al.[10].

Furthermore, several previous studies have suggested 
DM has a mild impact on semen quality. For example, 
DM may have its effects on male reproductive function 
by endocrine control of spermatogenesis, sperm 
maturation, and impairment of ejaculation[11].

The prevalence of abnormalities such as azoospermia, 
oligospermia, and aspermia may be higher in patients 
with DM and in elderly men[12-14]. In our study, men 
who were older at the time of the questionnaire were 
more likely to have experienced infertility, suggesting 
that the longer the duration of T1D, the greater 
likelihood of infertility in these men. Moreover, this 
study highlighted some common DM sequalae such 
as renal failure and micro/macroalbuminuria, which 
were found to be significantly more prevalent among 
infertile men. It is worth mentioning that this study 
did not report specific sperm abnormalities as it is 
questionnaire-based study (Appendix 1).

The findings of this study reinforce the importance of 
understanding the common metabolic pathway linking 
DM and male infertility. Cross-sectional studies have 
shown that even at the time of a fertility evaluation, 

men with reduced fertility already present with more 
medical comorbidities than their fertile peers[15,16]. 
The observation of a higher baseline prevalence of 
DM among men with infertility is concordant with 
this evidence. However, the relationship between male 
infertility and overall health is rather complex as several 
confounders may affect both. For example, as both age 
and smoking are known to affect semen quality[14] 
and diabetes risk[17], the results of this study must 
be interpreted with caution. Furthermore, a genetic 
link between DM and male infertility may exist as a 
recent study identified over 100 genes associated with 
both male infertility and several disease mechanisms, 
including metabolic disease pathways[18]. Further, as 
many genes are expressed during male germline cell 
differentiation, it seems plausible that possible mutations 
in this process could lead to both male infertility and 
risk of DM[19].

Our study does have some limitations that should be 
noted. Our questionnaire did not ask specific questions 
about when these patients experienced infertility, so it is 
difficult to interpret whether men in the infertile group 
experienced infertility in their 20s and 30s, or at an older 
age. However, we did find that men with advancing 
age were more likely to experience infertility, which we 
believe suggests that a greater duration with T1D might 
increase the likelihood of infertility. Secondly, our study 
questionnaire does not specify whether the difficulty 
conceiving a child was due solely to male factors or also 
female factors. Finally, this study asked patients with 
T1D to identify whether they had experienced trouble 
conceiving and whether they had undergone fertility 
testing, but did not report specific abnormalities, which 
would have been of interest. We believe more research 
should be conducted in the future to look at specific 
fertility abnormalities associated with DM, while our 
study attempted to address the overall prevalence of 
infertility in this population.

Conclusions
This study highlights the prevalence of male infertility 
among men with T1D. Beyond age, there were no 
independent clinical predictors for male infertility 
among men with T1D; however, men with clinical 
evidence of diabetes-associated renal compromise were 
more likely to be infertile. Further studies of fertility in 
this growing, at-risk population are warranted.

142 SIUJ  •  Volume 2, Number 3  •  May 2021 SIUJ.ORG

ORIGINAL RESEARCH

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Infertility

The next questions are about infertility history
This will be shown to participants ≥ 18 years old.

    Do not wish to answer the following questions

1. Have you ever had problems  
conceiving a child?

   Yes   No 

2. Have you ever received  
infertility testing?

   Yes   No 

  If you answered yes to question 2,  
please answer 2a.

 2a.     Were the test results normal?

   Yes   No

APPENDIX 1. 

Participating research centres

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Does Type 1 Diabetes Affect Male Infertility: Type 1 Diabetes Exchange Registry-Based Analysis

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