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Keywords:

  • cryptorchidism;
  • fertility;
  • orchiopexy;
  • semen analysis;
  • undescended testes

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Participants and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. Conflict of interest
  10. References

Men with a history of congenital undescended testes (UDT) have an increased risk of fertility problems. Despite no definitive proof, current guidelines recommend early surgical intervention because this may have a positive effect on future fertility potential by preventing degenerative changes of the testes in early life. Also surgical intervention facilitates observability of the testes in view of possible malignancy. We evaluated testicular function in adult men with previous UDT treated at different ages before puberty. A long-term follow-up study of men with previous UDT was performed. Andrological evaluation included medical history taking, physical examination, scrotal ultrasound, determination of reproductive hormones, and semen analysis. Findings were compared with those of a control group of men with normal testicular descent. The influence of age at orchiopexy on future fertility parameters was evaluated in a multivariate regression analysis. 62 men were included of whom seven had had bilateral UDT. Twenty-four patients had had their orchiopexy before the age of 24 months of whom eight men had it before 12 months of age. Forty-eight men had had unsuccessful luteinizing-hormone-releasing-hormone (LHRH) nasal spray treatment during childhood, whereas 14 of 24 men operated before 24 months of age had not received LHRH treatment before orchiopexy. Fertility potential in men with a history of UDT is compromised in comparison with controls. We could not detect any influence of age at orchiopexy on fertility parameters. However, the number of patients operated before the age of 12 months is limited. This study does not support the assumption that early orchiopexy results in better fertility potential.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Participants and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. Conflict of interest
  10. References

Congenital undescended testis (UDT), also known as congenital cryptorchidism, occurs in 2–9% (Virtanen & Toppari, 2008) of male newborns. Spontaneous descent may occur in the first year of life, especially during the first 3 months (Virtanen & Toppari, 2008). UDT may lead to fertility problems later in life, especially in bilateral cases (Cortes & Thorup, 1991; Cortes, 1996; Lee, 2005). Randomized controlled studies have shown overall low success rates of hormonal therapy. Therefore, hormonal therapy is no longer recommended for the treatment of cryptorchidism (Ritzen, 2007). The standard treatment today is a surgical one: orchiopexy. Judging from histopathological degenerative changes in the testis by the 18th month of life, early orchiopexy may prevent testicular maldevelopment and thus have a beneficial effect on fertility (Cortes, 2000). Current guidelines recommend that orchiopexy should be performed before the age of 18 months (Tekgul, 2011).

We report a long-term follow-up study aimed at measuring fertility potential in men treated for congenital UDT at various prepubertal ages. We aimed to answer the following : (i) What is the extent of fertility damage in men with a history of UDT in comparison with a healthy control group? (ii) What is the influence of age at orchiopexy on the fertility parameters in adult life?, and (iii) Are there any differences in fertility parameters between men with unilateral and bilateral UDT?

Participants and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Participants and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. Conflict of interest
  10. References

Participants

Subjects from a placebo-controlled study on effects of luteinizing-hormone-releasing-hormone (LHRH) nasal spray, carried out between 1982 and 1985 were assessed for eligibility (deMuinck Keizer-Schrama, 1986). Those subjects were boys aged between 1 and 12 years with unilateral or bilateral UDT who underwent orchiopexy at different ages before puberty if the UDT did not descend after LHRH nasal spray treatment.

To increase discriminative power of the present study we also assessed eligibility of men operated on before 2 years of age in our hospital between 1982 and 1990, applying the same inclusion and exclusion criteria as for the LHRH-study (deMuinck Keizer-Schrama, 1986). A total of 225 men, with 252 congenital UDT, could be contacted for the present study.

The presence of retractile testes had been excluded under general anaesthesia. Surgical findings were available for all men, classified as published previously (Hazebroek, 1987). In short:Intraoperative location: (i) Absent; (ii) Intraabdominal; (iii) Inguinal canal; (iv) External annulus; (v) Superficial inguinal pouch.Processus vaginalis: (i) Closed; (ii) Small open; (iii) Wide open.

Methods

All 225 men were sent an invitation by post, including the request to return the enclosed response card. A reminder was sent to those who did not return the response card. Additional information about the study was sent to men who considered participating in the study. Again, eligible candidates who did not respond were contacted by post. Those who declined participation were asked for their reasons and were invited to fill in a questionnaire regarding fertility and risk factors for subfertility or infertility other than UDT. Participation involved a single hospital visit including medical history taking, physical examination, scrotal ultrasound, venous puncture. and semen sample delivery.

History

We focused on risk factors for fertility problems other than cryptorchidism. Special attention was paid to attempting fatherhood, duration of child-wish (months), and time to first pregnancy (TTP) (months).

Physical examination and scrotal ultrasound

Two investigators (including first author) conducted a physical examination and performed a scrotal ultrasound to measure testicular volume and to check for the presence of a varicocele in a standardized procedure using a high-resolution duplex ultrasound machine (Toshiba Nemio model 17, type SSA-550A; Toshiba Medical Systems Corporation, Otawara-shi, Tochigi, Japan) with a transducer frequency of 7.5–12 MHz. A testicular volume of 15 mL or greater was considered normal.

Blood analysis

A venous blood sample was taken, preferably before 10:00 am and before 11:00 am at the latest. Serum samples were assayed for luteinizing hormone (LH, reference value 1.5–8 IU/L) and follicle stimulating hormone (FSH, reference value 2–7 IU/L) using fluorescence-based immunometric methods (Immulite 2000; Siemens-DPC, Los Angeles, CA, USA), testosterone (reference value 10–30 nmol/L) using a coated tube radioimmunoassay (Siemens-DPC), and inhibin B (InhB, reference value ≥150 ng/L) using an enzyme-immunometric method (Oxford BioInnovation, Oxford, UK).

Semen analysis

A semen sample produced by masturbation after a 3–5-day ejaculatory abstinence was analysed according to the recommendations from the most recent WHO (2010) manual. Within one hour, after liquefaction, semen volume (reference value ≥1.5 mL), sperm concentration (reference value ≥15 × 106/mL), total sperm count (reference value ≥39 × 106/ejaculate), progressive motility (reference value ≥32%), and morphology (reference value ≥4% normal forms) were determined.

Control group

Fifty-three healthy men without a history of UDT served as a control group. These men took part in a study investigating fatherhood in tall men (n = 153) after the use or non-use of sex steroid treatment in adolescence to reduce final height (Hendriks, 2010). These men had the same evaluation as the study participants, except for morphological evaluation of semen.

In that study, men with endocrine or metabolic disorders were excluded. As a control group we used the 56 men who did not receive sex steroids, of whom we excluded three men referable to a history of orchiopexy or treatment with radio- or chemotherapy (Hendriks, 2010).

Statistical analysis

Continuous variables were tested with the Mann–Whitney U test; categorical variables with Fisher's exact test. First, characteristics of participants were compared with those of non-participants. Second, participants' information regarding medical history and paternity was compared with that of non-participants who returned the questionnaire.

The Kaplan–Meier survival method served to estimate the probability of conception in participants and controls; the Wilcoxon (Breslow) test served to test if the participants' average conception rate differed from that in controls. Furthermore, fertility parameters (testicular volume, endocrinological values, and semen parameters) were compared between the two groups. In case of bilateral UDT, testicular volume was taken to be the mean of the volumes of the two testes.

Age at surgery was analysed as a continuous variable in several multivariate logistic regression analyses performed to establish relationships between fertility parameters (testicular volume, endocrinological results, and all semen parameters) and age at surgery. Fertility parameters were analysed by means of the chance of being below or above the reference value. Known confounders such as smoking, varicocele, and body mass index (BMI) were corrected for in these analyses (Shiels, 2009). Other independent variables were uni-/bilateral UDT, intraoperative testis position, and patency of processus vaginalis. For all analyses a two-sided p-value of less than 0.05 was considered statistically significant.

Ethics

The study was reviewed and approved by the Medical Ethical Review Board at Erasmus University Medical Center in Rotterdam (MEC number 2004-206). Written informed consent was obtained from all men who agreed to participate in the study.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Participants and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. Conflict of interest
  10. References

Participants

Sixty-two of the 225 eligible men (28%) participated (Fig. 1). Non-participants stated time constraints and bothersomeness of the investigations as main reasons for refusal. Age at orchiopexy, present age, and distribution of unilateral and bilateral UDT did not significantly differ between participants and non-participants (Table 1). The participation rate of men operated at younger age was not statistically different from that of men operated at older age when the cut-off was set at 12, 18 or 24 months of age at orchiopexy (age ≤ 12 months p-value 0.248; age ≤ 18 months p-value 0.176; and age ≤ 24 months p-value 0.652).

image

Figure 1. Flowchart for eligible patients and inclusions.

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Table 1. Characteristics of study participants and non-participants
 Participants N = 62Non-participants = 163p-valuea,b
  1. Values are expressed as median (range) or number (per cent).

  2. a

    Mann–Whitney test.

  3. b

    Fisher's exact test.

Age(years)
Age at recruitment27.7 (20.1–37.9)27.1 (18.5–37.2)0.25a
Age at surgery3.0 (0.1–14.6)2.3 (0.0–11.9)0.35a
Unilateral or Bilateral
Unilateral55(89)141(86.5)0.82b
Bilateral7(11)22(13.5)

Thirty-eight men who responded, but did not participate returned the questionnaire. Present age and age at orchiopexy did not significantly differ between participants and men who returned the questionnaire without further participation. Proportions of men attempting fatherhood, number of pregnancies, TTP, and proportions of men having an active child-wish at time of recruitment did not differ between the participants and non-participants returning the questionnaire. In neither group TTP exceeded 12 months. The duration of child-wish was significantly longer in participants than that in non-participants, who had returned the questionnaire [median (range); 12 (2–36) vs. 2 (0–5) months respectively; p-value 0.03].

Comparison of fertility parameters; participants with a history of unilateral UDT vs. healthy controls (Table 2)

Physical examination and scrotal ultrasound: Participants' volume of the previously UDT, measured by ultrasound was significantly smaller than the controls' mean testicular volume. Moreover, the volume of the normally descended contralateral testis was also significantly smaller compared with the control group. All men in the control group had a normal testicular consistency; 29 of 55 participants (53%) had uni- or bilateral soft testicular consistency (p-value < 0.001). Varicocele occurred more often in the control group, but the difference was not statistically significant.

Endocrine function: Endocrinological data were obtained from 54 participants; one participant refused blood sampling. Both Leydig cell function represented by LH and testosterone as well as Sertoli cell function represented by FSH and InhB did not differ between the control group and the participants.

Semen analysis: Five men in the control group had undergone vasectomy and therefore semen analysis was not performed. Participants had a significantly lower median concentration, more often oligospermia according to the WHO-reference values (2010), and less progressive motile spermatozoa than the control group. None of the participants was diagnosed with azoospermia.

Paternity: A higher proportion of men in the control group attempted fatherhood. More men in the control group succeeded in comparison with the participants, however, this difference was not statistically significant (participants: 6 of 11 (55%) vs. controls: 25 of 29 (86%); p-value 0.08). Based on low numbers of men who attempted fatherhood, TTP, and duration of child-wish were not statistically significantly different between these two groups (data not shown). The result of the Breslow test, which took time to conception into account was that the control group had a higher probability of conceiving, however, this was not statistically significant (0.07 pregnancy/month for unilateral group vs. 0.12 pregnancy/month for controls; p-value 0.28) (Fig. 2).

image

Figure 2. Cumulative probability of conception of the unilateral UDT group and control group. (p-value 0.28).

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Influence of age at orchiopexy on fertility parameters

The Participants' median age at orchiopexy was 3.0 years (range 0.1–14.6 years). Eight boys had been operated on before the age of 1 year, 12 before 18 months of age, and 24 before the age of 2 years.

Physical examination and scrotal ultrasound: In the complete group as well as in the unilateral group only, testicular volume of the previous UDT, testicular volume of the contralateral normally descended testis, testicular consistency, and incidence of varicocele did not statistically differ when cut-off values for age at surgery were used (12 months, 18 months, and 24 months at operation).

Endocrine function: Both in the complete group of participants and the unilateral group only, hormone levels except LH did not differ at the cut-off values of 12 months, 18 months or 24 months at orchiopexy. LH levels were significantly lower in the group operated at older age when applying cut-off values for age at orchiopexy (12 months, 18 months, and 24 months at operation) (Mann–Whitney U test).

Semen analysis: Both in the complete group of participants and in the unilateral group only, sperm parameters did not differ at the cut-off values of 12 months, 18 months, and 24 months at orchiopexy.

Multiple regression analyses: Figure 3 shows scatter plots of the relations of age at orchiopexy with testicular volume, FSH, InhB, and sperm concentration respectively. We could not detect any influence of age at orchiopexy on these fertility parameters.

image

Figure 3. Testicular volume, FSH (IU/L), inhibin B (ng/L) and sperm concentration (106/mL) in relation to age at orchiopexy (years).

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Table 3 presents the results of the multiple regression analyses for age at orchiopexy as a continuous variable and its effect on testicular volume, hormonal values, and semen parameters.

Table 2. Background characteristics and study findings in participants with unilateral UDT and control group
Unilateral UDT groupControl group p-valuea . b
  1. Values are expressed as median (range) or number (per cent).

  2. a

    Mann–Whitney test.

  3. b

    Fisher's exact test.

  4. The significant p-values (<0.05) are expressed in Bold.

Characteristics N = 55 N = 53
 Age at recruitment (years)27.3 (20.1–36.7)36.7 (23.0–49.8) <0.001 a
 Age at surgery (years)2.8 (0.1-10.3)
 Currently smoking19 (35)7 (13) 0.01 b
 Venereal disease0 (0)3 (6)0.11b
Physical examination N = 55 N = 53
 Height (cm)184.5 (167.5–204.0)196.0 (179.9–208.8) <0.001 a
 Weight (kg)80.4 (66.0–122.2)101.5 (67.0–135.0) <0.001 a
 BMI (kg/m2)23.9 (18.4–35.3)26.4 (19.2–35.1) <0.001 a
 Monotestis60
 Normal testicular consistency29 (53)53 (100) <0.001 a
Ultra sound N = 55 N = 53
 Testis volume (mL)9.6(2.7–22.9)15.8(8.1–27.0) <0.001 a
 Testis volume, contralateral testis (mL)13.8(6.0–28.1)15.8(8.1–27.0) 0.01 a
 Varicocele5 (8)10 (19)0.17b
Hormone levels N = 54 N = 53
 LH (IU/L)3.3(1.1–10.3)3.6(1.3–7.3)0.59a
 FSH (IU/L)4.8(0.7–21.2)4.5(1.6–13.9)0.72a
 Testosterone (nmol/L)14.9(8.2–28.7)15.4(7.6–34.7)0.86a
 Inhibin B (ng/L)157.0(22.0–554.0)168.0(96.0–488.0)0.14a
Semen analysis N = 55 N = 48
 Concentration (106/mL)21.0(0.1–276.0)54.5(0.1–213.0) <0.001 a
 Oligozoospermia
  <15 × 106/mL18 (33)4 (8) 0.04 b
 Total sperm count (106)67.8(0.2–496.8)201.3(0.6–880.0) <0.001 a
 Low total sperm count
  <39 × 106/ejaculation20 (36)5 (9) <0.001 b
Progressive motility (%)41.0(0–69)52.0(9–91) <0.001 a
 Astenospermia
  <32%18 (33)10 (19)0.19b
Paternity N = 55 N = 52
 Attempt to fatherhood11 (20)29 (56) <0.001 b
  Successful6 (55)25 (86)0.08b
  Unsuccessful5 (45)4 (14)
Table 3. Multiple regression analysisa of fertility parameters as function of age at surgery
 Number of menbOdds ratio95% Confidence intervalp-value
  1. a

    Multiple logistic regression including other independent variables; smoking, varicocele, BMI, uni- or bilateral UDT, intraoperative testis position and patency processus vaginalis.

  2. b

    Number of missing data: BMI not known in two patients, endocrinological values not known in one patient, morphology not tested in 10 participants.

Volume UDT601.040.88–1.220.66
Hormone levels
 LH590.810.60–1.110.20
 FSH591.110.91–1.360.31
 Testosterone591.070.82–1.410.60
 Inhibin B591.140.95–1.370.17
Semen analysis
 Concentration601.050.88–1.240.60
 Motility600.920.78–1.090.33
 Morphology520.960.82–1.130.63
Table 4. Fertility parameters in participants operated before 24 months of age; men receiving LHRH nasal spray before orchiopexy and men not receiving LHRH nasal spray
Men receiving LHRH nasal spray prior to orchiopexyMen not receiving LHRH nasal spray p-valuea . b
  1. Values are expressed as median (range) or number (per cent).

  2. a

    Mann–Whitney test.

  3. b

    Fisher's exact test.

  4. c

    Cryptorchid testis in case of unilateral UDT, mean testis volume in case of bilateral testis volume.

  5. d

    Only unilateral UDT.

  6. The significant p-values (<0.05) are expressed in Bold.

Characteristics N = 10 N = 14
 Age at recruitment (years)26.1 (25.4–27.3)23.6 (20.1–28.2) 0.01 a
 Age at surgery (years)1.8 (1.5–2.0)0.7 (0.1–1.8) <0.001 a
Ultra sound N = 10 N = 14
 Testis volume (mL)8.1 (2.7–21.8)c 15.5(6.6–22.9) 0.03 a
 Testis volume, contralateral testis (mL)12.9(8.6–28.1)d 12.8(6.5–24.8)0.84a
Hormone levels N = 10 N = 14
 LH (IU/L)4.6(1.8–10.3)4.3 (1.4–8.0)0.95a
 FSH (IU/L)6.1(0.7–10.8)4.0(2.2–28.8)0.73a
 Testosterone (nmol/L)16.4 (9.3–28.7)15.3 (12.2–20.9)0.66a
 Inhibin B (ng/L)130.5 (91.0–417.0)173.0 (22.0–395.0)0.86a
Semen analysis N = 10 N = 14
 Concentration (106/mL)18.5 (0.2–72.0)18.0 (0.2–112.0)0.77a
 Oligozoospermia
  <15 × 106/mL4 (40)6 (43)1.00b
 Total sperm count (106)58.4 (0.3–331.2)72.2 (0.6–343.3)0.91a
 Low total sperm count
  <39 × 106/ejaculation4 (40)6 (43)1.00b
 Progressive motility (%)41.5 (5–60)31.5 (1–60)0.48a
 Astenospermia
  <32%2 (20)7 (50)0.21b
N = 9 N = 12
 Morphology (%)5 (0–9)3.5 (0–10)0.39a
  <4%3 (33.3)6 (50)0.66b

Age at orchiopexy had no significant influence on fertility parameters, after correction for known confounders and other independent variables (smoking, varicocele, BMI, uni-/bilateral UDT, intraoperative testis position, and patency of processus vaginalis).

Influence of bilateral UDT on fertility parameters; comparisons with controls and unilateral UDT

Seven men of 62 had a history of bilateral UDT, two men had had an orchiopexy before the age of two and five men were operated after 2 years of age.

Physical examination and scrotal ultrasound: The mean testicular volume in the group of men with bilateral UDT was statistically smaller in comparison with the control group [median (range): 7.6 mL (6.2–18.1) vs. 15.8 mL (8.1–27.0) respectively; p-value 0.01]. Five of seven men (71%) had uni- or bilateral soft testicular consistency compared with none of the men in the control group (p-value < 0.001). No differences in physical examination or scrotal ultra sound results were found when comparing the bilateral group with the unilateral group.

Endocrine function: In comparison with the control group, the bilateral group showed values, which indicate worse Sertoli cell function represented by both FSH and InhB. The median FSH-value was 8.2 IU/L (range 1.6–28.8) for the bilateral UDT group and 4.5 IU/L (range 1.6–13.9) for the control group (p-value 0.05). The median InhB value in the bilateral group was significantly lower compared with that in the control group: median (range) 125.0 ng/L (1.0–364.0) vs. 168.0 ng/L (96.0–488.0) respectively (p-value 0.02).

When comparing participants with unilateral UDT with participants with bilateral UDT no statistically significant differences in endocrine function were found. Borderline significant values were found for FSH and InhB. FSH was higher in the bilateral group [median (range) 8.2 IU/L (1.6–28) vs. 4.8 IU/L (0.7–21.2); p-value 0.08]. InhB was lower in the bilateral group [median (range) 125 ng/L (1.0–364.0) vs. 157.0 ng/L (22.0–554.0); p-value 0.09].

Semen analysis: In comparison with the control group, men with previously bilateral UDT had significantly lower sperm concentration [median (range): 0.6 × 106/mL (0.1–364.0) vs. 54.5 × 106/mL (0.1–213.0); p-value < 0.001] and motility [median (range): 36% (1–60) vs. 52% (9–91); p-value 0.02].

Sperm concentration in men with bilateral UDT was significantly lower than that in men with unilateral UDT [median (range): 0.6 × 106/mL (0.1–46.0) vs. 21.0 × 106/mL (0.1–276.0); p-value 0.03]. When the cut-off value for oligospermia stated in the WHO 2010 guideline was used, no significant difference was found between men with unilateral and those with bilateral UDT.

Fertility parameters in participants operated before 24 months of age; comparison of men receiving LHRH nasal spray before orchiopexy vs. men not receiving LHRH nasal spray (Table 4)

Of the 62 men included in this study 24 men had had the orchiopexy before the age 2 years. 14 men of 24 did not receive LHRH nasal spray prior to the orchiopexy. These men were significantly younger at orchiopexy compared with the men who had received LHRH nasal spray.

Physical examination and scrotal ultrasound: Testicular volume of the previously cryptorchid testis was significantly smaller in the group treated with LHRH nasal spray prior to orchiopexy compared with the testis volume of the men not treated with LHRH nasal spray. No difference was found when comparing testicular volume of the normally descended testis between the group treated with LHRH nasal spray and men not treated with hormonal therapy. The volume of the previously UDT of men not treated with hormonal therapy did not statistically differ between men operated before or after 12 months of age: [median (range) 13.1 mL (6.6–18.8) and 15.9 mL (12.7–22.9); p-value 0.25].

Endocrine function: No differences could be observed in endocrine function between men who were and were not treated with LHRH nasal spray prior to orchiopexy.

Semen analysis: No significant differences were found in semen parameters when comparing men who had had LHRH nasal spray before surgery and men who were only treated with orchiopexy.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Participants and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. Conflict of interest
  10. References

The most important finding of this study is the lack of an age-dependent effect of orchiopexy on fertility parameters in men with previous congenital UDT.

Fertility potential can be evaluated using semen analysis. In this study, both semen concentration and motility were significantly lower in participants than that in the control group. Cortes et al. published data on semen parameters in patients with unilateral and bilateral UDT. In comparison with our study, the sperm parameters found in their studies were better (Cortes & Thorup, 2001; Cortes, 1991). However, in those studies the age at surgery was relatively high, which might indicate a higher proportion of men having acquired UDT instead of congenital UDT. Also it is not clear whether retractile testes have been excluded in those studies. Many studies have been published on semen parameters in patients with UDT. Such studies are not always easy to compare because of several reasons; (i) different therapeutic strategies, (ii) variation in reporting the results (mean values, median values or percentage normal/abnormal), (iii) the WHO-reference values for semen analysis have changed over time, (iv) uncertainty whether groups contain only congenital UDT or also acquired UDT, (v) groups may contain unilateral or bilateral UDT or a combination of both, (vi) unclear about the exclusion of retractile testis (Canavese, 2009; Cortes & Thorup, 2001; Cortes, 1991; Coughlin, 1999; Engeler, 2000; Gracia, 2000; Lee & Coughlin, 2002; Taskinen, 1997; Vinardi, 2001). In this study, men with retractile testis or acquired UDT were excluded and this might be an explanation for our low sperm concentration in comparison with the literature.

Although some studies have suggested that orchiopexy at younger age results in better semen parameters (Canavese, 2009; Engeler, 2000; Taskinen, 1997) results of this study show no favourable effect of early treatment on semen characteristics, in line with other studies (Coughlin, 1999; Gracia, 2000; Lee & Coughlin, 2002; Vinardi, 2001). No study which evaluates age at surgery as a continuous variable finds statistically significant correlations with semen parameters (Coughlin, 1999; Gracia, 2000; Lee & Coughlin, 2002; Vinardi, 2001). Two studies found an effect of age at surgery for patients with bilateral UDT, but not for unilateral UDT (Engeler, 2000; Taskinen, 1997). Canavese et al., in a study on orchiopexy within the first 2 years of life found that age at surgery was inversely related to sperm concentration and motility (Canavese, 2009).

Different results on the effect of hormonal treatment on fertility potential or germ cell development have been reported. In the study by Canavese, men operated at a younger age had significantly more often received hormonal therapy (LHRH nasal spray and subsequently human chorionic gonadotropin i.m.) prior to surgery (Canavese, 2009). In a study by Hadziselimovic et al., in which the effect of LHRH nasal spray on testicular descent was analysed, neither a stimulatory effect nor an inhibitory effect on the number of germ cells was seen (Hadziselimovic, 1980). This in contrast to Cortes et al., who found a negative effect on germ cells in 1–3-year-old boys with cryptorchidism after gonadotropin releasing hormone (GnRH) (Cortes, 1996). They hypothesized that these young boys may be sensitive for exogenous GnRH stimulation resulting in increased FSH, LH, and testosterone, which may have a negative impact on germ cells. In this study, all participants who were operated after 24 months of age received LHRH nasal spray prior to orchiopexy, although 10 of the 24 men who were operated before 24 months received this hormonal treatment and 14 men did not. We hypothesize that our LHRH treatment, at younger age is very unlikely to have influenced later fertility because at the time of treatment no evidence of stimulation of the hypothalamo-pituitary-gonadal axis was found (deMuinck Keizer-Schrama, 1986). At adult age, only testicular volume of the previously UDT appeared to be smaller in the group treated with LHRH nasal spray prior to surgery compared with men treated with only orchiopexy. Thereby testis volume of the contralateral testis in case of unilateral UDT did not differ between men with or without hormonal therapy. Endocrinological values and semen analysis did not show statistical differences between participants receiving hormonal therapy and those not receiving hormonal therapy below the age of 24 months.

Testicular volume is an accepted predictor for spermatogenesis (Bahk, 2010). In this study, Participants' testicular volume was significantly lower than that of the control group. However, age at orchiopexy did not influence testicular volume in adulthood. As stated above, the group of men of this study who had not received hormonal therapy had larger testicular volumes. When evaluating the age effect in this group also no effect of age at orchiopexy on adult testicular volume could be found. Other studies on testicular volume and age at orchiopexy imply that younger age at surgery might result in higher testicular volume (Caroppo, 2005; Engeler, 2000; Taskinen & Wikstrom, 1996). To our knowledge, only one randomized prospective study showed a beneficial effect of early orchiopexy on testis volume. At 4 years of age testis volume was larger in patients operated at 9 months compared with patients operated at the age of 3 years (Kollin, 2007). However, the follow-up period differed between the two groups and the question remains whether or not adult testicular volume would still be different between the two groups and if so, what the effect would be on fertility.

Other indicators of spermatogenesis are FSH and InhB levels. UDT have been related to lower InhB and higher FSH levels (Lee, 2001). In this study, FSH levels and InhB levels did not significantly differ between participants and the control group. Age at orchiopexy was not significantly correlated with FSH and InhB levels. This is in contrast to a study by Coughlin et al., in which age at surgery negatively correlated with InhB and positively with FSH levels (Coughlin, 1999). However, in that study a multivariate analysis correcting for known confounders was not performed. Some histological studies not only suggest maldevelopment of germ cells, but also of Leydig cells (Huff, 1993). Hormonal evidence for Leydig cell dysfunction was found in adult patients after a late orchiopexy (Lee & Coughlin, 1995). In this study, age at orchiopexy had no statistically significant influence on Leydig cell function.

Men with a history of bilateral UDT face more fertility problems than do men with previously unilateral UDT (Gracia, 2000; Taskinen, 1997). In this study, sperm concentration was significantly lower in patients with bilateral UDT (Mann–Whitney U test). Multivariate analyses, however, showed that having uni- or bilateral UDT did not predict the chance of having a sperm concentration below or above 15 × 106/mL. The analysis might be flawed, however, by low number of men with bilateral UDT (N = 7).

Another way to evaluate fertility is looking at paternity. Lee et al. reported paternity proportions of 89.7, 65.3, and 93.2% in, respectively, unilateral UDT, bilateral UDT, and healthy controls (Lee, 2001). Likewise, in this study, paternity in the participants was borderline significantly lower than that in the control group. Lee et al. found that age at orchiopexy was not correlated with paternity (Lee, 2005). Ascribable to the small numbers of men who fathered children or attempted fatherhood in our study we cannot confirm this result.

Early operation is hypothesized to have a favourable effect on germ cell development. In the first year of life, neonatal germ cells transform into spermatogonia. This process is important for future fertility because spermatogonia are the progenitor cells for future spermatogenesis. In boys with UDT, the process of germ cell maturation is impaired (Huff, 1993). Germ cell numbers start to deviate as from 18 months old (Cortes, 2000). Based on these observations the recommended age for orchiopexy was gradually lowered to under the age of 12 months (Cortes, 2000). The Nordic consensus recommends surgery between 6 and 12 months of age, but not earlier given the possibility of spontaneous descent during the first months of life (Ritzen, 2007). The question remains why early operation, which might prevent histological changes had no beneficial effect on fertility parameters in this study. As only eight patients were operated on or before the age of 12 months, a definite conclusion cannot be drawn. Our results suggest a congenital malfunction of the testis that cannot be influenced by reducing duration of the non-scrotal position. Huff et al. found similar, but less severe histological changes in the contralateral normally descended testis (Huff, 2001). Also Zivkovic found significantly lower numbers of germ cells per tubule in contralateral normally descended testes in patients with unilateral UDT in comparison with spontaneously descended testes in healthy controls (Zivkovic, 2010). Indeed, both testes might be affected in case of unilateral UDT, for in our study the volume of the contralateral normally descended testis was also significantly smaller than that of controls.

A limitation of our study is the fairly low inclusion rate (28%). The inclusion rate in other studies varied between 29 and 73% (Canavese, 2009; Cortes & Thorup, 2001; Cortes, 1991; Engeler, 2000; Gracia, 2000; Taskinen, 1997). Three studies had a higher number of participants than our study of (Cortes & Thorup, 2001; Coughlin, 1999; Gracia, 2000). A possible explanation for our low inclusion rate is the long interval between operation and inclusion. Thereby, in our study patients had no regular check-ups after operation. Patients might be more motivated to participate when the treatment is more recent or when follow-up is more frequent. In this study, age at orchiopexy, uni- or bilateral cryptorchidism, and current age did not differ between men who did not respond and men who responded by questionnaire or participated. This suggests that the group of men who completed follow-up is a representative part of the whole group. The number of men having an active child-wish did not differ between the men who responded by questionnaire and the men participating. Selection bias may have occurred, however, because the Participants' duration of child-wish was significantly longer than that of those who only returned the questionnaire. The duration of child-wish is not to be mistaken for actual clinical infertility. The questionnaire was not validated to produce such information. Selection bias is always an issue in fertility studies, because men with fertility problems might be more motivated than fertile men to participate. We presume that the risk for selection bias because of fertility problems is the same in both the participants and the control group (the participation rate in the control group was 31%) as the control group was not a group of chart-selected, mostly fertile men. A high occurrence of varicocele in tall men is described (Delaney, 2004). In this study, the incidence of varicocele in the control group was twice as high compared with that in the patient group. In our multivariate regression analyses we corrected for varicoceles.

In conclusion, the present long-term follow-up study could not find a relation between the age at orchiopexy and fertility parameters for patients with a history of unilateral UDT, most of them after unsuccessful LHRH treatment. As only eight patients had had their orchiopexy in the first year of life, this conclusion has to be taken with caution for patients operated before 12 months of age. This conclusion might also not be legitimate for bilateral UDT because no more than seven men with bilateral UDT participated. As congenital UDT are not expected to descend spontaneously after the first year of life, orchiopexy is needed for psychosocial reasons, prevention of torsio, and better observability of the testes in view of possible malignancy in young adulthood.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Participants and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. Conflict of interest
  10. References

The authors thank Ko Hagoort for editorial assistance. They also thank Mark Wildhagen for his skilful work with the database.

Author contribution

  1. Top of page
  2. Abstract
  3. Introduction
  4. Participants and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. Conflict of interest
  10. References

Study concept and design: van Brakel, Hazebroek, de Muinck Keizer-Schrama, Dohle.

Data collection: van Brakel, Hazebroek.

Statistical analysis: van Brakel, Kranse.

Analysis and interpretation of data: van Brakel, Kranse, de Muinck Keizer-Schrama, Hazebroek, Dohle.

Drafting of the manuscript: van Brakel, Kranse.

Critical revision of the manuscript for important intellectual content: Kranse, de Muinck Keizer-Schrama, Hendriks, de Jong, Bangma, Hazebroek, Dohle.

Literature search: van Brakel.

Figures: van Brakel, Kranse.

Conflict of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Participants and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. Conflict of interest
  10. References

G.R. Dohle is the associate editor of Andrology. Other authors have nothing to disclose.

Funding

None.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Participants and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contribution
  9. Conflict of interest
  10. References
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