Type 1 diabetes mellitus and sperm quality: A case‐control study

Abstract

Background

The potential impact of diabetes mellitus type 1 (DM1) on male fertility is currently poorly defined. Hyperglycaemia and insulin deficiency may affect spermatogenesis. Some evidence suggests that men with DM1 have a significant reduction in progressive sperm motility, sperm morphology and semen volume, without significant changes in sperm concentration and count, but definite data are lacking.

Objectives

To evaluate the impact of DM1 on clinical parameters related to male fertility and semen analysis.

Materials and methods

We compared a court of 42 male DM1 patients with 43 nondiabetic subjects overlapping in age and remaining clinical data in an observational case‐control study. All subjects underwent a comprehensive andrological reproductive evaluation, including medical history, physical examination, and semen analysis. We collected biochemical data in all patients with DM1, while diabetic patients with any alteration in semen parameters underwent sperm culture and scrotal ultrasound. In addition, all men completed the IIEF‐5 questionnaire (International Index of Erectile Function‐5) and the AMS (Aging Male Symptom score) questionnaire.

Results

Patients with DM1 had a higher prevalence of infertility, erectile dysfunction and worse semen parameters compared with controls. In particular, semen volume, total sperm count, and total and progressive sperm motility were significantly lower (p < 0.001, p = 0.003, p = 0.048, and p = 0.022 respectively). In addition, the rate of semen anti‐sperm antibody positivity, the AMS score and FSH levels were higher.

Discussion and conclusion

Several mechanisms may contribute to these semen alterations in DM1 patients, such as oxidative damage to spermatogenesis, seminal infections and pelvic neurological changes. These data suggest that patients with DM1 should be counselled from an andrological‐reproductive point of view.

1. INTRODUCTION

Type 1 diabetes mellitus (DM1) is a metabolic disorder characterised by chronic hyperglycaemia and altered glucose metabolism due to a deficit in insulin secretion by pancreatic β‐cells. ¹ This condition results from the destruction of pancreatic β‐cells, either by autoimmune or idiopathic mechanisms, leading to absolute insulin deficiency. ² In Italy, the incidence of DM1 is rising, with 10−40 cases per 100,000 people per year with an overall prevalence of about 0.5%. ³ The incidence of DM1 varies widely in different geographical areas, with Northern Europe considered to have a high incidence of 30−60 cases per 100,000 people per year. ² Although autoimmune diseases affect more women than men, DM1 has a similar frequency in both sexes, with a slight male predominance (53% of cases). In Italy, the estimated prevalence is 1.2 affected men per 1000 of the male population. ³

Couple infertility is defined as the inability to achieve pregnancy after at least 12 months of regular unprotected intercourse. ⁴ Currently in Italy, about 1 in 5 couples (15–20% of the fertile population) experience fertility issues. ⁴ This statistic is on the rise and environmental, social, and lifestyle factors are thought to play a role. ⁴ Infertility is due to female or male causes in 35−40% and 30−35% of cases respectively, whereas couple problems (idiopathic infertility) in the remaining 20−25%. ⁴ Male infertility can have pre‐testicular, testicular, and posttesticular causes. ⁵ Assessment of male infertility in a couple should begin with both a general and andrological history and a testicular examination. Semen analysis is fundamental to the assessment of male fertility, providing information on semen quality and quantity compared with World Health Organization (WHO) reference values, ⁴ , ⁶ and on the overall condition of the seminal tract, thus guiding the male reproductive diagnostic pathway. ⁵ In addition to the semen analysis, other key tests to assess male fertility include gonadal hormone assessment, sperm culture and testicular ultrasound. ⁵

A recent review and meta‐analysis conducted by our research group highlighted the available literature data on “Type 1 diabetes mellitus (DM1) and male fertility”. ⁷ Although in vitro or animal studies have observed that hyperglycaemia and insulin deficiency may alter spermatogenesis, few clinical studies have assessed the impact of DM1 on male fertility. ⁷ With regard to semen analysis, our meta‐analysis showed that compared with controls men with DM1 have a significant reduction in progressive sperm motility, sperm morphology, and semen volume (the latter bordering on significance), without significant changes in sperm concentration and count. ⁷ To date, studies that have comprehensively and appropriately evaluated the reproductive aspect in men with DM1 are limited, often dated, and not without methodological limitations in terms of diagnostic accuracy. ⁷ Therefore, the potential impact of DM1 on male fertility is currently poorly defined. In light of this, the aim of the present study is to further evaluate the semen quality in patients affected by DM1.

2. METHODS

2.1. Patients

The study protocol followed standard clinical practice and the tenets of the Declaration of Helsinki. This observational case‐control study was approved by the Ethics Committee of the Hospital of Brescia (Italy; study code NP 4985 and subsequent amendments). Forty‐two men with the diagnosis of autoimmune DM1, according to the position statement of the American Diabetes Association, ⁸ were prospectively enrolled upon outpatient evaluation at the Unit of Endocrinology of the Hospital of Brescia (Italy) and followed at the Unit of Metabolic Diseases of the same University Hospital from 1 June 2021 to 31 May 2022. Inclusion criteria involved: diagnosis of DM1, age between 18 and 40 years, absence of known forms of testicular damage, such as Klinefelter's syndrome, cryptorchidism, testicular trauma or torsion or cancer, orchitis, pituitary disorders, recent or current infections, tumours, organ failure, chemotherapy, radiotherapy, gonadal interfering drugs or hormone treatment. We preselected diabetic patients under the age of 40. This decision was made in advance to minimize potential confounding factors such as habits and/or illnesses known to adversely affect sperm quality. Additionally, it aligns with the median age of paternity in our country, which is 37 years old. ⁹

In particular, diabetic patients were enrolled according to the absence of uncompensated glycaemic symptoms (polyuria, polydipsia, weight loss) and overt diabetic acute or chronic complications (cardiovascular events, diabetic retinopathy, nephropathy and neuropathy). At the same time, 43 nondiabetic age‐matched men, taking part in a reproductive andrological health screening programme at our University Hospital, were enrolled as control. All subjects provided a signed informed consent for the participation in the study.

All subjects underwent a physical examination, including the measurement of the waist circumference (wc), weight and height, calculation of the body mass index, assessment of gynaecomastia, testicular ultrasound examination, including the assessment of testis volume and seminal tracts evaluation. All patients received a complete anamnesis to assess age, years of diabetes, current smoking, daily alcohol consumption, paternity, concomitant infertility (defined as the failure to conceive after > 12 months of regular unprotected intercourse), ⁴ miscarriages or need for assisted reproduction, type of diabetes treatment (multiple injections or insulin pump), comorbidities (current or past phimosis, varicocoele, hypertension on antihypertensive therapy, dyslipidaemia on lipid‐lowering therapy, hypothyroidism on replacement therapy) and sexual symptoms (decreased libido and erection, premature ejaculation). In addition, all men completed the International Index of Erectile Function‐5 (IIEF‐5) questionnaire to assess erectile function. ¹⁰ Erectile dysfunction was assigned for IIEF‐5 scores ≤21. The Aging Male Symptom score (AMS) questionnaire was used to assess the presence of andrological and general discomfort symptoms with increasing scores. ¹¹ Testicular ultrasound colour Doppler evaluation was performed in our Unit by the same operator and using high resolution and high‐frequency linear probes (7.5–14 MHz, Samsung Ugeo H60) to assess testicular volume [estimated using the ellipsoid formula (0.52 × length × width × depth)], echogenicity, seminal tract changes, scrotal disease and caput epididymis dimension. ¹² Testicular hypotrophy was defined as right testicular volume <12 cc and/or left testicular volume <11 cc ¹² ; dilation of the caput epididymis was considered if the dimension was >12 mm. ¹²

2.2. Semen analysis

Semen analysis was performed in accordance with the WHO laboratory manual for the examination and processing of human semen—VI Edition 2021. ⁶ All patients were instructed to maintain 2−7 days of sexual abstinence before collecting an ejaculate for investigation. In addition, all subjects were informed about the importance of reporting any missed ejaculate fractions, and their responses were collected. Semen specimens were collected at the laboratory of the Unit of Endocrinology of the Hospital of Brescia (Italy) and maintained at 37 °C at least 30 min before the initiation and during the analysis. Semen analysis was performed using a phase‐contrast microscope, at a magnification of 200×, by the same trained operator using a Makler Sperm Counting Chamber. ⁶ The following parameters were examined: semen volume (mL), pH, normal or altered viscosity/fluidification/agglutination, sperm concentration (10⁶cells/mL) and total number of spermatozoa per ejaculate (10⁶), total and progressive motility (%), typical morphology (%), viability (%), presence of anti‐sperm antibodies (ASA) evaluated by mixed agglutination test, and round red blood cells. Semen alteration was classified, according to whether the seminal parameters fell below the fifth percentile of the reference population, ⁶ into oligozoospermia (sperm concentration < 16 × 10⁶/ml or total number < 39 × 10⁶ per ejaculate), asthenozoospermia (total motility < 42% or progressive motility < 30%), teratozoospermia (< 4% typical morphology), azoospermia (absence of spermatozoa, even after semen centrifugation), hypoposia (sperm volume < 1.4 mL), and pathological presence of ASA (> 50%). ⁶ Microbiological semen assessment culture was performed in our laboratory to detect the presence of pathological seminal bacteria (chlamydia, mycoplasma) or human papillomavirus (HPV). ⁴ Only diabetic patients with seminal changes were subjected to sperm culture and scrotal ultrasound in accordance with clinical practice, ⁴ (available in 21 and 12 men, respectively).

2.3. Metabolic and hormonal evaluation

Patients with DM1 underwent fasting blood sample in the morning, between 8:00 am and 10:00 am, in our hospital laboratory for the following biochemical assays: glycated haemoglobin (HbA1c), creatinine, alanine transaminase (ALT), aspartate transaminase (AST), glutamyl transferase (GGT), prostate‐specific antigen (PSA), luteinising hormone (LH), follicle‐stimulating hormone (FSH), total testosterone (TT), estradiol (E2), sex hormone‐binding globulin [SHBG, to assess calculated free testosterone (cFT) based on SHBG and albumin concentration according to the Vermeulen formula ¹³ ] and 25‐OH vitamin D (high‐pressure liquid chromatography assay). All assessments were performed by routine chemiluminescence microparticle immunoassay. Testicular hormonal impairment was defined for LH levels > 9.4 UI/L, ¹⁴ TT levels < 3.5 ng/mL or cFT levels < 65.0 pg/mL, ⁷ and FSH levels > 8.0 UI/L. ¹⁵ Hypovitaminosis D was defined for 25‐OH vitamin D levels < 30.0 ng/mL. ¹⁶

2.4. Statistical analysis

The Statistical Package for the Social Sciences software IBM SPSS Statistics, version 26.0) was used for statistical analysis. The continuous variables were normally distributed (by the Kolmogorov–Smirnov test) and were expressed as mean and standard deviation, while categorical variables were expressed as percentages. Comparative analyses (between case and control variables) were performed using T‐tests or ANOVA tests (for continuous variables) and Chi‐square tests or Fisher's Exact tests (for categorical variables). Correlation analyses were performed using Pearson's correlation (for continuous variables) and point‐biserial correlation (for categorical variables). A multivariate analysis of variance (MANOVA) was performed to investigate the impact of diabetes‐related parameters on hormonal status and sperm quality.

A p‐value < 0.05 was considered significant.

3. RESULTS

Table 1 shows the clinical data of DM1 patients and controls. The diagnosis of DM1 occurred at an age of 18.8 ± 9.1 years, while the andrological evaluation took place at 31.9 ± 5.9 years old. Consequently, the mean duration of DM1 before enrolment in the study was 13.1 ± 8.4 years.

TABLE 1.

Comparison of clinical variables in patients with DM1 vs. controls.

	DM1 (n = 42)	Controls (n = 43)	p‐value
Age (years)	31.9 ± 5.9	30.8 ± 2.9	0.283
BMI (kg/m2)	24.8 ± 4.0	23.9 ± 2.9	0.264
Waist circumference (cm)	89.8 ± 12.0	87.8 ± 8.3	0.381
Smoke (yes/no)	13 (30.9%)	9 (20.9%)	0.291
Alcohol (yes/no)	9 (21.4%)	7 (16.3%)	0.543
Hypertension (yes/no)	4 (9.5%)	0	0.055
Dyslipidaemia (yes/no)	3 (7.1%)	1 (2.3%)	0.360
Hypothyroidism (yes/no)	6 (14.3%)	1 (2.3%)	0.058
Paternity (yes/no)	13 (30.9%)	7 (16.3%)	0.111
Couple infertility (yes/no)	6 (14.3%)	1 (2.3%)	0.045
Sexual symptoms (yes/no)	12 (28.6%)	3 (6.9%)	0.009
PE (yes/no)	2 (4.7%)	3 (6.9%)	0.664
Gynecomastia (yes/no)	1 (2.4%)	1 (2.3%)	0.751
Phimosis (yes/no)	9 (21.4%)	2 (4.6%)	0.021
Varicocoele (yes/no)	12 (28.6%)	14 (32.5%)	0.690
IIEF (score)	21.4 ± 4.8	24.2 ± 1.8	<0.001
IIEF‐5 ≤ 21	10 (23.8%)	3 (6.9%)	0.031
AMS (score)	33.0 ± 11.3	23.1 ± 5.9	<0.001
Right testicular volume (cc)	16.8 ± 3.8	16.6 ± 4.4	0.799
Left testicular volume (cc)	16.3 ± 3.5	16.0 ± 4.5	0.797
Seminal tract alterations (yes/no)	15 (35.7%)	17 (39.5%)	0.716

Note: Statistically significant values are in bold.

Abbreviations: AMS, Aging Male Symptoms; BMI, body mass index; DM1, type 1 diabetes mellitus; ds = standard deviations; IIEF‐5, International Index of Erectile Function; PE, premature ejaculation.

A higher prevalence of couple infertility was found in the DM1 population respect to controls (14.3% vs 2.3%, respectively, p = 0.045), whereas no significant differences in paternity rates were observed between the two groups (p = 0.111). No subject reported miscarriages or the need for assisted reproductive technologies. Diabetic patients had a higher prevalence of phimosis (21.4% vs 4.6%, p = 0.021), with no other anamnestic‐objective clinical differences. Patients with DM1 also had a lower IIEF‐5 score (21.4 ± 4.8 vs 24.2 ± 1.8, p < 0.001), a higher prevalence of erectile dysfunction (23.8% vs 6.9%, p = 0.031), and a higher AMS score (33.0 ± 11.3 vs 23.1 ± 5.9, p < 0.001). No significant differences were observed between the two groups in the prevalence of hypertension, hypercholesterolaemia and hypothyroidism.

Semen examination was available in 39 diabetic subjects because 3 men (7%) presented with anejaculation (Table 2). In detail, semen volume (2.4 ± 1.3 vs 3.8 ± 1.4, p < 0.001), total number of spermatozoa (219.6 ± 159.6 vs 358.9 ± 246.6, p = 0.003), total sperm motility (49.2 ± 17.7 vs 57.1 ± 17.7, p = 0.048) and progressive sperm motility (42.7 ± 21.8 vs 53.2 ± 18.5, p = 0.022) were significantly lower in the DM1 population compared with controls. A higher prevalence of hypoposia (15.4% vs 0%, p = 0.008) and asthenozoospermia (33.3% vs 11.6%, p = 0.018) were observed in DM1 patients (Table 2).

TABLE 2.

Comparison of semen parameters in patients with DM1 vs. controls.

	DM1 (n = 39)	Controls (n = 43)	p‐value
Semen volume (mL)	2.4 ± 1.3	3.8 ± 1.4	<0.001
Semen pH	7.8 ± 0.4	7.8 ± 0.3	0.895
Impaired viscosity	25 (64.1%)	20 (46.5%)	0.109
Alterations in appearance‐fluidification‐agglutination	22 (56.4%)	20 (46.5%)	0.370
Concentration (×106/mL)	89.8 ± 59.5	97.6 ± 60.5	0.561
Total number of spermatozoa (×10 6 )	219.6 ± 159.6	358.9 ± 246.6	0.003
Total motility (%)	49.2 ± 17.7	57.1 ± 17.7	0 .048
Progressive motility (%)	42.7 ± 21.8	53.2 ± 18.5	0.022
Normal sperm morphology (%)	8.8 ± 4.9	9.1 ± 4.7	0.798
Hypoposia	6 (15.4%)	0 (0%)	0.008
Oligozoospermia	6 (15.4%)	2 (4.6%)	0.102
Asthenozoospermia	13 (33.3%)	5 (11.6%)	0.018
Teratozoospermia	5 (12.8%)	3 (6.9%)	0.373
Sperm viability (%)	78.1 ± 10.6	80.0 ± 13.2	0.476
Presence of exfoliation cells	12 (30.8%)	9 (20.9%)	0.308
Round cells (×10 6 /mL)	0.6 ± 0.9	0.9 ± 0.6	0.081
Red cells (×10 6 /mL)	0.1 ± 0.1	0.05 ± 0.1	0.221
ASA (%)	9.6 ± 21.0	2.3 ± 3.6	0.262
ASA +	15 (38.4%)	4 (9.3%)	0.003
ASA > 50%	3 (7.7%)	0	0.241

Note: Statistically significant values are in bold.

Abbreviations: ASA, sperm auto‐antibodies; DM1, type 1 diabetes mellitus; SD, standard deviations.

Taking into account diabetes‐related parameters (i.e., age at diabetes diagnosis, years of diabetes disease, HbA1c, insulin pump treatment, etc.), logistic regression analysis showed that HbA1c was the only potential predictor for asthenozoospermia (p = 0.044; Exp(B) 4.989; 95% CI: 1.042–23.894), hypoposia (p = 0.015; Exp(B) 2.613; 95% CI: 0.961–7.107), oligozoospermia (p = 0.060; Exp(B) 7.591; 95% CI: 0.917–62.840), and teratozoospermia (p = 0.033; Exp(B) 0.076; 95% CI: 0.007–0.815). None of the diabetes‐related parameters evaluated was a potential predictor of low TT and high LH.

DM1 patients had a higher rate of ASA positivity in semen (38.4% vs 9.3%, p = 0.003), with no other significant differences (Table 2). No significant effect of comorbidities (hypertension, hypercholesterolaemia, hypothyroidism, varicocoele) on semen parameters was observed (Table 3).

TABLE 3.

Effect of comorbidities on semen parameters in DM1 patients.

	Hypertension			Dislipidemia			Hypothyroidism			Varicocoele
	Yes	No	p‐value	Yes	No	p‐value	Yes	No	p‐value	Yes	No	p‐value
Hypoposia	2 (50.0%)	4 (11.4%)	0.104	1 (33.3%)	5 (13.9%)	0.403	1 (16.7%)	5 (15.2%)	0.661	2 (20.0%)	4 (13.8%)	0.636
Oligozoospermia	0	6 (17.1%)	0.489	0	6 (16.7%)	0.597	0	6 (18.2%)	0.339	2 (20.0%)	4 (13.8%)	0.636
Asthenozoospermia	2 (50.0%)	11 (32.4%)	0.424	2 (66.7%)	11 (31.4%)	0.265	3 (50.0%)	10 (31.3%)	0.328	3 (30.0%)	10 (35.7%)	0.532
Impaired viscosity	2 (50.0%)	23 (65.7%)	0.609	1 (33.3%)	24 (66.7%)	0.289	4 (66.7%)	21 (63.6%)	0.635	6 (60.0%)	19 (65.5%)	0.754
Alterations in agglutination	0	17 (48.6%)	0.089	1 (33.3%)	16 (44.4%)	0.598	2(33.3%)	15 (45.5%)	0.465	5 (50.0%)	12 (41.4%)	0.721
ASA > 50%	0	2 (6.7%)	0.824	0	2 (6.5%)	0.881	0	2 (7.1%)	0.716	0	2 (8.0%)	0.568
Alterations in pH	1 (25.0%)	7 (20.0%)	0.617	1 (33.3%)	7 (19.4%)	0.508	3 (50.0%)	5 (15.2%)	0.088	1 (10.0%)	7 (24.1%)	0.653
Teratozoospermia	1 (25.0%)	5 (14.7%)	0.513	0	6 (17.1%)	0.588	2 (33.3%)	4 (12.5%)	0.234	0	6 (21.4%)	0.136

Abbreviations: ASA, sperm auto‐antibodies.

Patients presented with anejaculation had age of onset of DM1 (21.0 ± 6.5 vs 18.9 ± 9.3 yrs., respectively p = 0.282), mean duration of DM1 (15.3 ± 7.8 vs 13.4 ± 8.6 yrs., respectively p = 0.559), and age of enrolment in the study (36.3 ± 3.1 vs 32.3 ± 6.0 yrs., respectively, p = 0.146) comparable with DM1 patients without an ejaculation. Differently, HbA1c was significantly higher (8.57% vs 7.07%, p < 0.001). No significant differences were found by referring to the type of insulin therapy (33.3% vs 37.2% had an insulin pump, p = 0.860) and smoking habits (2/3 vs 12/43 patients, p = 0.216).

A multivariate analysis of variance (MANOVA) was performed to investigate the impact of diabetes‐related parameters on hormonal status and sperm quality (Table 4). There was a statistically significant difference according to age of onset (F [13, 3] = 274.7, p = 0.005) and mean duration of DM1 (F [13, 3] = 130.0, p = 0.005) on the combined dependent variables, but not significant difference according to HbA1c levels was found (p = .197). When the results for the dependent variables were considered separately, semen volume and cFT were significantly impaired both by age of onset and mean duration of DM1. The latter also impaired total sperm motility (Table 4).

TABLE 4.

Multivariate analysis to identify diabetes‐related parameters that impact sperm parameters and hormonal variables.

		ANOVA
	Dependent variable	Sum of square	Mean squared	F	p‐value	MANOVA
Age at DM1 diagnosis	TT	0.2	0.2	0.1	0.787	F value (13,3) = 274.7 ηp 2 = 0.999 p < 0.05
	cFT	3754.9	3754.9	7.2	0.017
	LH	3.7	3.7	0.8	0.381
	FH	20.9	20.9	1.4	0.252
	Semen volume	0.5	0.5	0.5	0.048
	Semen pH	0.2	0.2	0.7	0.415
	Concentration	388.3	388.3	0.1	0.766
	Total number of spermatozoa	1953.9	1953.9	0.1	0.809
	Total motility	3.2	3.2	0.0	0.923
	Progressive motility	2.4	2.4	0.0	0.936
	Vitability	5.1	5.1	0.1	0.820
	Normal sperm morphology	3.6	3.6	0.3	0.624
	ASA	235.3	235.3	0.7	0.430
Age from DM1 diagnosis	TT	8.4	8.4	2.9	0.112	F value (13,3) = 130.0 ηp2 = 0.998 p < 0.05
	cFT	7996.4	7996.4	15.2	0.001
	LH	14.7	14.7	3.2	0.094
	FH	17.1	17.1	1.2	0.299
	Semen volume	2.6	2.6	2.5	0.035
	Semen pH	0.5	0.5	2.4	0.146
	Concentration	1079.3	1079.3	0.3	0.621
	Total number of spermatozoa	11571.9	11571.9	0.4	0.557
	Total motility	259.0	259.0	0.8	0.045
	Progressive motility	279.8	279.8	0.8	0.387
	Vitability	104.8	104.8	1.1	0.310
	Normal sperm morphology	5.7	5.7	0.4	0.540
	ASA	10.2	10.2	0.0	0.868
HbA1c levels	TT	4.8	4.8	1.7	0.218	F value (13,3) = 3.0 ηp 2 = 0.929 p = 0.197
	cFT	9.5	9.5	0.0	0.895
	LH	0.6	0.6	0.1	0.715
	FH	11.4	11.4	0.8	0.392
	Semen volume	0.3	0.3	0.3	0.602
	Semen pH	0.0	0.0	0.1	0.730
	Concentration	1259.2	1259.2	0.3	0.594
	Total number of spermatozoa	12339.1	12339.1	0.4	0.545
	Total motility	0.1	0.1	0.0	0.987
	Progressive motility	3.4	3.4	0.0	0.923
	Vitability	88.1	88.1	0.9	0.350
	Normal sperm morphology	18.0	18.0	1.3	0.281
	ASA	252.8	252.8	0.7	0.413

Abbreviations: ASA, sperm auto‐antibodies; cFT, calculated free testosterone; FSH, follicle‐stimulating hormone; LH, luteinizing hormone; TT, total testosterone.

Biochemical, hormonal and ultrasonographic data of DM1 patients are reported in Table 5. In detail, hypovitaminosis D was found in 64.3% of patients, impaired LH and FSH levels were found in 4.8% and 11.9% of patients, respectively, and reduced serum testosterone levels in only one patient.

TABLE 5.

Biochemical and ultrasonographic data in patients with DM1.

	DM1 (n = 42)
HbA1c (%)	7.2 ± 0.9
Creatinine (mg/dL)	0.8 ± 0.1
eGFR (ml/min)	107.2 ± 25.1
ALT (U/L)	22.1 ± 5.8
AST (U/L)	34.6 ± 9.1
GGT (U/L)	36.3 ± 7.2
PSA (ng/mL)	0.6 ± 0.4
LH (UI/L)	5.2 ± 2.9
FSH (UI/L)	5.7 ± 4.1
TT (ng/mL)	6.6 ± 1.8
SHBG (nmol/L)	53.3 ± 17.3
cFT (pg/mL)	103.3 ± 26.5
TT < 3.5 ng/mL	1 (2.4%)
cFT < 65 pg/mL	1 (2.4%)
LH > 9.4 UI/L	2 (4.8%)
FSH > 8 UI/L	5 (11.9%)
E2 (ng/L)	29.4 ± 13.7
25 OH Vitamin D (ng/mL)	24.0 ± 10.3
25 OH Vitamin D < 30 ng/mL	27 (64.3%)
Sperm culture + (n = 21)	10/21 (47.6%)
Bacteria+	5/21 (23.8%)
HPV+	6/21 (28.6%)
Scrotal ultrasound (n = 12) Testicular hypotrophy	2/12 (16.7%)
Non‐homogeneous testicular echostructure	2/12 (16.7%)
Epididymis head > 12 mm	2/12 (16.7%)
Epididymis head cyst	5/12 (41.7%)
Nonhomogeneous seminal tract echostructure	4/12 (33.3%)
Hydrocele	3/12 (25.0%)
Left varicocoele	5/12 (41.7%)

Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; cFT, calculated free testosterone; DM1, type 1 diabetes mellitus; E2, estradiol; eGFR, estimated glomerular filtration rate; FSH, follicle‐stimulating hormone; GGT, glutamyl transferase; HbA1c, glycated haemoglobin; HPV, Human Papilloma Virus; LH, luteinizing hormone; PSA, serum prostate‐specific antigen; SD, standard deviation; SHBG, sexual hormone binding globulin; TT, total testosterone.

In the DM1 population, sperm culture was positive in 47.6% of cases and seminal HPV was positive in 28.6% of patients (Table 5). Table 5 also shows the prevalence of testicular ultrasound changes in the diabetic population (testicular hypotrophy, epididymal cyst and left varicocoele in 16.7%, 41.7% and 41.7% of cases, respectively).

In DM1 patients, a positive correlation was observed between years of DM1 and FSH levels (0.354, p = 0.027), which correlated negatively with sperm concentration (−0.358, p = 0.03); significant correlations were found between semen volume and HbA1c levels (−0.443, p = 0.003), TT (0.358, p = 0.025) and AMS score (−0.382, p = 0.012). In the diabetic population, cFT levels correlated negatively with age (−0.62, p = 0.001) and years of DM1 (−0.394, p = 0.047); the presence of erectile dysfunction correlated positively with age (0.374, p = 0.015) and HbA1c levels (0.370, p = 0.016). In the diabetic population, no significant clinical‐biochemical‐seminal differences were observed between the basal‐bolus insulin therapy group (n = 26) and the pump‐treated patients (n = 16).

4. DISCUSSION

The present study showed worse semen parameters in young men with DM1 compared with controls. In accordance with the majority of literature data, we evidenced the reduction of some parameters such as semen volume, ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ total sperm count, ¹⁷ total sperm motility, ¹⁷ , ¹⁸ , ¹⁹ , ²² and progressive sperm motility. ²¹ , ²² , ²³ There were also three cases of anejaculation and an increased prevalence of hypoposia and asthenozoospermia. These data are consistent with observations from population studies indicating that couples with at least one partner with DM1 have a reduced fertility rate. ²⁴ , ²⁵ , ²⁶ However, we didn't show a reduction in paternity rates, as observed in previous larger studies. ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ In addition, we observed a correlation between semen volume and serum TT and between semen volume and HbA1C levels. These data suggest that, as reported in the literature, hypoposia may occur mainly in patients with worse metabolic profile glycaemia ¹⁸ , ²¹ and lower testosterone levels. ¹⁵ These semen alterations may be due to several mechanisms by which DM1 could alter spermatogenesis. ⁷ , ²⁸ In particular, in vitro and animal studies have shown that hyperglycaemia and insulin deficiency lead to a dysregulation of testicular cellular glucose uptake, with an increase in biochemical products of glycation (AGE, advanced glycation end product) and reactive oxygen species (ROS). ²⁹ , ³⁰ These mechanisms induce chronic inflammation and oxidative stress at the level of the seminiferous tubules with consequent damage to the mitochondria of spermatozoa. ²⁰ , ³¹ , ³² These changes may explain the reduction in sperm motility observed in patients with DM1, as the mitochondrion is a central cellular energy source. ³² The increase in ROS at the testicular level also leads to oxidative damage to the polyunsaturated fatty acids of the sperm membrane (peroxidation), which can induce cell apoptosis and subsequent alteration of spermatogenesis. ³² , ³³ The link between testicular oxidative stress and male infertility is well established. ³⁴ , ³⁵ Another mechanism that may predispose patients with DM1 to altered semen parameters is semen infection. ³⁴ , ³⁶ , ³⁷ It is known that hyperglycaemia can promote urogenital infections, particularly accessory seminal tract infections, ³⁶ , ³⁸ which can lead to male reproductive problems. ⁵ Specifically, it is known that a positive sperm culture for seminal pathogenic bacteria is associated with altered seminal parameters as well as rheological changes. ⁵ , ³⁶ In addition, seminal infection with HPV can reduce sperm motility and increase evidence of ASA positivity. ³⁹ , ⁴⁰ Our study evidenced a higher ASA rate in DM1 patients than controls (p = 0.003). In agreement with Jiang et al. ⁴¹ and Sucato et al., ⁴² this could be due to the higher prevalence of infection detected (47.6%) in DM1 patients. These last data could also explain the high rates of hypoposia and asthenozoospermia, as previously suggested by Garolla et al. ³⁹ , ⁴⁰ The increased rates of HPV infection were found slightly higher than what was reported in studies of the general male population of sexually active age, ⁴⁰ suggesting that the diabetic population should receive appropriate counselling and management. Another factor that may alter the seminal parameters in patients with DM1 is the pelvic neurological abnormalities secondary to diabetic neuropathy. ⁴³ , ⁴⁴ This condition may be associated with retrograde ejaculation/anejaculation (we found it in three of our patients) and altered epididymal contraction (resulting in dilatation in 16.7% of cases). ³⁶ Regarding the hormonal profile in patients with DM1, our data confirmed a significant prevalence of elevated FSH and hypovitaminosis D. ⁷ , ¹⁷ , ⁴⁵ The positive correlation between FSH levels and duration of diabetic disease may indicate a progressive deterioration of testicular function and spermatogenesis over the years. ¹⁵ , ⁴⁶

Our study also confirms a worse erectile function and greater evidence of erectile dysfunction in patients with DM1, data already reported in the literature, although described in few studies. ²⁷ , ⁴⁷ Finally, we found a worse AMS score in patients with DM1, data not reported in the literature. The AMS score does not represent a routine tool in the diabetological‐andrological setting but it could indicate a worse perceived general andrological well‐being in these subjects and therefore deserves to be used. ¹¹

The main limitations of our study were the limited number of cases enrolled, the absence of sperm DNA fragmentation index assessment, the absence of hormonal assessment, sperm culture and testicular ultrasound in the control group. Nevertheless, in our study, patients with DM1 of reproductive age underwent a complete andrological evaluation, including seminal fluid examination according to the WHO standard (6^th edition 2021). Another strength of our study is the presence of a control group.

5. CONCLUSION

In our study, 42 men with diabetes mellitus type 1 underwent a comprehensive andrological reproductive evaluation, including medical history, objective examination, semen analysis, gonadal hormone testing, sperm culture and testicular ultrasound. Patients with diabetes mellitus type 1 had a higher prevalence of erectile dysfunction and worse semen parameters compared with controls, although our data evidenced a similar paternity rate. In particular, semen volume, total sperm count, and total and progressive sperm motility were significantly lower. In addition, the rate of semen anti‐sperm antibody positivity, the Aging Male Symptom scores and follicle‐stimulating hormone levels were higher. Several mechanisms may contribute to this finding, such as oxidative damage to spermatogenesis, seminal infections and pelvic neurological changes. These data, although they need to be confirmed in a larger case, suggest that patients with diabetes mellitus type 1 should be treated from an andrological‐reproductive point of view.

AUTHOR CONTRIBUTIONS

Paolo Facondo and Angela Girelli collected the data. Paolo Facondo and Andrea Delbarba analyzed the data. Anelli Valentina, Francesca Bambini, Caterina Buoso, Elisa Gatta, Andrea Delbarba and Paolo Facondo wrote the paper and critically revised the paper. Carlo Cappelli and Alberto Ferlin conceptualized the study, interpreted the data, and critically revised the paper.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

Delbarba A, Anelli V, Bambini F, et al. Type 1 diabetes mellitus and sperm quality: A case‐control study. Andrology. 2025;13:208–216. 10.1111/andr.13681

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.