Cryptorchid Men Research Articles

MP01-09 GENE DOSAGE CHANGES IN CRYPTORCHID MEN WITH NONOBSTRUCTIVE AZOOSPERMIA

You have accessJournal of UrologyCME1 Apr 2023MP01-09 GENE DOSAGE CHANGES IN CRYPTORCHID MEN WITH NONOBSTRUCTIVE AZOOSPERMIA Aaron Brant, Caroline Kang, Anna Mielnik, Marisol O'Neill, Meade Haller, Peter Schlegel, and Dolores Lamb Aaron BrantAaron Brant More articles by this author , Caroline KangCaroline Kang More articles by this author , Anna MielnikAnna Mielnik More articles by this author , Marisol O'NeillMarisol O'Neill More articles by this author , Meade HallerMeade Haller More articles by this author , Peter SchlegelPeter Schlegel More articles by this author , and Dolores LambDolores Lamb More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003212.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Copy number variations (CNVs) are structural chromosomal defects causing microdeletions or microduplications. CNVs in the dosage-sensitive genes ADCY2, ADCY9, CRKL, KCTD13, RBFOX2, and ZEB2 occur more frequently in men with genitourinary anomalies such as cryptorchidism and hypospadias compared to the general male population. To evaluate the association of these CNVs with spermatogenic failure, the prevalence of CNVs in men with history of cryptorchidism who underwent microdissection testicular sperm extraction (mTESE) for non-obstructive azoospermia (NOA) was defined. METHODS: Whole blood DNA samples were collected from 101 men with cryptorchidism and NOA who presented for (mTESE) and two fertile control men. TaqMan quantitative polymerase chain reaction was used to assess copy numbers of ADCY2, ADCY9, CRKL, KCTD13, RBFOX2, and ZEB2 with each reaction performed in triplicate. Relative quantification values were obtained using CopyCaller Software. Fisher’s exact test was used to compare CNVs in cryptorchid men with NOA compared to CNV prevalence in the general male population from the Database of Genomic Variants. RESULTS: Of the 101 patients, 44 (44%) had bilateral cryptorchidism, 57 (56%) had unilateral cryptorchidism, and 51 (50%) had sperm retrieved with mTESE. Six patients (5.9%) had CNVs detected. Two men had microdeletions of CRKL, one had a microdeletion of ZEB2, and one had a microduplication of ADCY2. Two men with bilateral cryptorchidism had multiple CNVs detected: one had microdeletions of ADCY2, ADCY9, and RBFOX2, and one had microdeletions of ADCY9, CRKL, ZEB2 and a microduplication of KCTD13. Four of the six patients with detected CNVs (67%) had sperm retrieved on mTESE. Compared the general male population, men with cryptorchidism and NOA had higher prevalence of CNVs in ADCY2 (p=0.002), ADCY9 (p=0.004), CRKL (p<0.001), and ZEB2 (p<0.001). CONCLUSIONS: Approximately 6% of adult men with a history of cryptorchidism and NOA had gene dosage changes in ADCY2, ADCY9, CRKL, KCTD13, RBFOX2, or ZEB2, with two-thirds of these men having successful sperm retrieval on mTESE. As many of these CNVs are syndromic, genetic counseling may be warranted for men found to carry them. The functional consequences of these gene dosage changes on adult spermatogenesis remain to be fully elucidated. Source of Funding: n/a © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e5 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Aaron Brant More articles by this author Caroline Kang More articles by this author Anna Mielnik More articles by this author Marisol O'Neill More articles by this author Meade Haller More articles by this author Peter Schlegel More articles by this author Dolores Lamb More articles by this author Expand All Advertisement PDF downloadLoading ...

The effects of tobacco consumption on paternity rates of adults with a history of cryptorchidism.

To determine the effect of tobacco consumption on paternity rates in men with a history of cryptorchidism. To compare the paternity rates between formerly unilateral, bilateral cryptorchid smokers, and nonsmokers. A retrospective cohort study of 153 men who had undergone orchiopexy between 1961 and 1985 at the Miguel Servet University Hospital (116 unilateral and 37 bilateral) and a control group of 100 men were evaluated by review of medical records and a questionnaire. A total of 197 men filled the questionnaire (76.7%). There was no difference in paternity rates between smokers compared to nonsmokers (P = 0.21). In the unilateral cryptorchid men (ULC) group, there is no difference in paternity rates when compared with the controls (P = 0.079) or when comparing ULC smokers to ULC nonsmokers (P = 0.35). In the bilateral cryptorchid men (BLC) group, there is no difference in paternity rates when compared to controls (P = 0.075) or when comparing BLC smokers to BLC nonsmokers (P = 0.36). When comparing according to consumption, there is no difference between mild, moderate or heavy smoker cases and controls. There is no difference in paternity rates between men with a history of cryptorchidism that consume tobacco compared to nonsmokers or controls. More studies are needed to determine the impact of tobacco consumption in formerly cryptorchid men.

Autophagy is increased in cryptorchid testis resulting in abnormal spermatozoa.

Autophagy is involved in spermatogenesis by regulating germ cell maturation. This catabolic process increases with hyperthermic conditions to prevent the accumulation of damaged organelles. Cryptorchidism is associated with impairment of germ cell maturation revealed by the presence of immature forms of sperm cells in ejaculates. The aim of the present study was to evaluate the status of autophagy in sperm cells from cryptorchid patients. Semen samples of cryptorchid patients and normozoospermic controls were analyzed by immunocytochemistry and electron microscopy. Autophagy proteins, autophagy-related protein 9 (ATG9) and microtubule-associated protein, 1A/1B-light chain 3 (LC3) were localized by immunocytochemistry on the acrosome and on the equatorial segment of sperm cells. LC3 was also detected in the midpiece of cryptorchid sperm tail. Autophagy substrate p62 protein was present in the acrosome and in the postequatorial segment of sperm in control samples, but not in the cryptorchid ones. Transmission electron microscopy revealed double-membrane-limited autophagosomes in postequatorial part of spermatozoa head and midpiece in cryptorchid samples. Partly degraded mitochondria were frequently discerned in autophagic vacuoles. In conclusion, autophagy is increased in sperm cells from patients with cryptorchid history comparatively to control. Our work provides insights into the role of autophagy in the maturation and survival of human male gametes in pathological conditions. Thus, regulating autophagy could represent a potential way to improve sperm quality in cryptorchid men.

Histopathology of Unilateral Cryptorchidism.

Defective mini-puberty inducing insufficient gonadotropin secretion is one of the most common causes of nonobstructive azoospermia in men suffering from congenital isolated unilateral or bilateral cryptorchidism. The aim of our study was to determine the risk for azoospermia by histologic criteria in a cohort of unilateral cryptorchid boys undergoing orchidopexy and bilateral testicular biopsy. We performed a retrospective analysis of data available in the library of the Cryptorchidism Research Institute, Liestal, Switzerland. Complete histological evaluations were available for 319 boys operated on for unilateral cryptorchidism with simultaneous biopsy of the contralateral descended testicle. The median age was 39 (5-192) months and 58 patients were <18 months of age. Forty-eight percent of undescended testis (UDT) and 21% of contralateral testis had no A dark (Ad) spermatogonia. Furthermore, in 11% of boys Ad spermatogonia were lacking in both testes. Positive correlation was found between the spermatogonia/tubule ratio of the UDT and contralateral testis (Spearman rank order correlation is 0.16, P = .003). The extent of alteration in the UDT correlated with the contralateral descended testis, indicating that unilateral cryptorchidism is a bilateral disease. Observed impaired transition from gonocytes into Ad spermatogonia indicates defective mini-puberty, providing one of explanations for azoospermia and infertility development in unilateral cryptorchid men.

Undescended testicle: An update on fertility in cryptorchid men.

Cryptorchidism or undescended testis is one of the most common anomalies encountered in paediatric urology and is estimated to affect 1 to 4 per cent of full term and upto 30 per cent of preterm male neonates. The associated problems of sub-fertility or infertility and malignant transformation have been recognized for long. Fertility is impaired after both unilateral and bilateral cryptorchidism. The reported paternity rates in adults are about two-third for unilateral undescended testis and less than one-third for bilateral disease. Over the last five decades, the concepts related to cryptorchidism have changed dramatically as knowledge about its effects has accrued from research conducted worldwide. The recommended age of orchidopexy has fallen progressively from adolescence to less than one year. The realization that the infantile testes are not in a state of 'suspended animation' and the recognition of the defect in the androgen dependent transformation of gonocytes into adult dark spermatogonia in cryptorchidism have been recognized as the primary cause of sub-fertility in these patients. This has paved the way for hormone therapy in an attempt to simulate the 'post-natal gonadotropin surge' or 'mini-puberty'. This review summarizes the current knowledge about the various factors affecting the fertility status in cryptorchidism with a particular focus on the derangements in the development and maturation of the germ cells and the role of surgery, hormone therapy and antioxidants in reversing these changes.

Spermatogenesis and cryptorchidism.

Cryptorchidism represents the most common endocrine disease in boys, with infertility more frequently observed in bilateral forms. It is also known that undescended testes, if untreated, lead to an increased risk of testicular tumors, usually seminomas, arising from mutant germ cells. In normal testes, germ cell development is an active process starting in the first months of life when the neonatal gonocytes transform into adult dark (AD) spermatogonia. These cells are now thought to be the stem cells useful to support spermatogenesis. Several researches suggest that AD spermatogonia form between 3 and 9 months of age. Not all the neonatal gonocytes transform into AD spermatogonia; indeed, the residual gonocytes undergo involution by apoptosis. In the undescended testes, these transformations are inhibited leading to a deficient pool of stem cells for post pubertal spermatogenesis. Early surgical intervention in infancy may allow the normal development of stem cells for spermatogenesis. Moreover, it is very interesting to note that intra-tubular carcinoma in situ in the second and third decades have enzymatic markers similar to neonatal gonocytes suggesting that these cells fail transformation into AD spermatogonia and likely generate testicular cancer (TC) in cryptorchid men. Orchidopexy between 6 and 12 months of age is recommended to maximize the future fertility potential and decrease the TC risk in adulthood.

Cancer risk in mothers of men operated for undescended testis.

BackgroundUndescended testis, or cryptorchidism, occurs in 2–5% of boys born at term, and by 12 months of age about 1% of all boys have manifest cryptorchidism. Several hormonal substances control this process and disruption of the foetal sex-hormones balance is a potential cause of undescended testis, however, to a great extent the aetiology of cryptorchidism is unclear.MethodologyTo study risk factors involved in the aetiology of undescended testis, we assessed cancer risk in 15,885 mothers of men operated for undescended testis in Sweden. Women were followed-up for a median period of 23 years during which 811 first primary malignancies occurred. Their cancer incidence was compared with that in the general population estimating standardized incidence ratio (SIR) and corresponding 95% confidence interval (CI).Principal FindingsThe overall cancer risk experienced by the mothers of cryptorchid men did not differ significantly from that of the general population (SIR = 0.94; 95% C.I. = 0.88–1.01). Specifically, there was a reduction in ovarian cancer risk (SIR = 0.72; 95% C.I. = 0.51–0.99), while the risk of lung (SIR = 1.38 95% C.I. 1.03–1.81) and biliary tract/liver cancer (SIR: 1.76, 95% CI: 1.03–2.82) were increased.ConclusionsAlthough we cannot rule out the role of chance, our data suggest a positive association between undescended testis and maternal lung cancer and a negative association with ovarian cancer, where the first may be partly attributable to smoking and the second to an altered hormonal milieu during pregnancy and thus both exposures may be risk factors for cryptorchidism.

Infertility in Cryptorchidism Is Linked to the Stage of Germ Cell Development at Orchidopexy

Background: Cryptorchidism represents the most common endocrine disease in boys, with infertility frequently observed in unilateral as well as bilateral forms. In this study, we examined the role of Ad (dark) spermatogonia for fertility in cryptorchid boys. The hypothesis to be proven was that boys lacking Ad spermatogonia will develop infertility despite a successful orchidopexy at an early age. Methods: To estimate total sperm count, one of the most predictive parameters of male fertility, we analyzed the ejaculatein 218 cryptorchid men and correlated it with the developmental stage of their germ cells at the time of successful surgery. Results: Abnormal sperm concentration (<40 × 10⁶/ejaculate) was found in half of the patients under the study. 47.5% of unilateral and 78% of bilateral cryptorchid males had their sperm concentration in the infertility range according to the WHO standards. If transformation into Ad spermatogonia had occured, age-related differences in the fertility outcome was observed. The younger the unilateral cryptorchid boys were at surgery, the higher their sperm count. Age-related difference was not found in the group of cryptorchid men having had no A dark spermatogonia at time of surgery, indicating that in this group a successful orchidopexy is insufficient to prevent infertility development and, in particular, the development of azoospermia. Conclusion: The presence of Ad spermatogonia at surgery is an excellent prognostic parameter for future fertility. Cryptorchid boys lacking these cells will develop infertility despite successful orchidopexy at an early age.

Immunostaining for placental alkaline phosphatase on fine‐needle aspiration specimens to detect noninvasive testicular cancer: a prospective evaluation in cryptorchid men

To assess, in a 12-year prospective study, the potential for early detection of testicular carcinoma in situ (CIS) by immunocytochemistry, using anti-placental alkaline phosphatase (PLAP) monoclonal antibodies on testicular fine-needle aspiration cytology (FNAC) specimens taken from a group of formerly cryptorchid patients, as such men are at greater risk of developing testicular cancer. Sixty-eight men who had had orchidopexy at the Urological Department of the University of Padova between 1975 and 1983 were evaluated first in 1993, by a protocol including a history, physical examination, testicular ultrasonography and serum tumour markers, to eliminate the presence of testicular cancer. In 57 of the 68 men, specimens taken from bilateral testicular FNAC were stained immunocytochemically using anti-PLAP monoclonal antibodies. After 8 years, the same protocol was repeated on the 57 men, and the follow-up was prolonged until March 2005 for men with previous positive PLAP immunostaining. In 1993, six of the 57 men, (10.5%) had unilateral positive immunostaining for PLAP. By 2001, none of these men had developed testicular cancer, while of the other 51 men, only one developed a nonseminomatous tumour. The uninterrupted surveillance of PLAP-positive men showed no overt cancer until March 2005. The present findings do not seem to confirm the reliability of PLAP immunostaining of testicular specimens from FNAC for detecting CIS. These findings might depend on the geographical variability of both CIS and testicular cancer incidence, as well as on the variable relationship between CIS and successive occurrence of invasive testis cancer.

Analysis of the DAZ gene family in cryptorchidism and idiopathic male infertility

Objective To investigate whether partial deletions of the DAZ gene family on the Y chromosome are associated with cryptorchidism, similar to that found for complete AZF deletions. Design Prospective study. Setting University hospital. Patient(s) A total of 193 azoospermic and severely oligozoospermic men: 95 with a history of cryptorchidism and 98 classified as idiopathic. Intervention(s) A two-part study for Y chromosome microdeletions was performed: a polymerase chain reaction (PCR)-based analysis for complete AZF deletions and partial DAZ gene analysis by PCR-restriction digestion assay for single-family variants. Main outcome measure(s) Presence and type of AZF deletions and number of DAZ genes present. Result(s) The frequency of complete AZF deletions was similar in idiopathic (13.3%) and cryptorchid men (11.6%), but partial DAZ deletions were found only in infertile subjects without cryptorchidism (7.1%). The testicular phenotype was similar in men with complete AZF deletions and partial DAZ deletions, therefore the contribution of the other AZF genes in determining the spermatogenic impairment is still unclear. Conclusion(s) Our findings suggest that the loss of only some copies of DAZ is sufficient to lead to severe male infertility, but it is not a frequent finding in cryptorchid men.

Expression of heat shock protein 70 in normal and cryptorchid human excurrent duct.

The Hsp70 heat-shock proteins are molecular chaperones that assist other proteins in their folding, transport and assembly into complexes. Most of these proteins are either constitutively expressed or induced by heat shock and other stresses. Heat shock proteins are required for spermatogenesis, and also protect cells from environmental hazards such as heat, radiation, and chemicals. The abdominal position of the cryptorchid testis provokes a temperature elevation which is detrimental to spermatogenesis and causes infertility. The consequences of such a stress on Hsp70 expression were evaluated in normal and cryptorchid epididymides and vas deferens. Hsp70-1 transcript from reproductive organs of normal and cryptorchid men was analysed by real-time quantitative RT-PCR, meanwhile Hsp70 protein was characterized by western blot and immunohistochemical staining analysis. Hsp70-1 mRNA and protein showed equal expression in all segments of normal epididymis and ductus deferens. Hsp70 was specific to basal cells in the epididymal epithelium. For cryptorchid patients, Hsp70-1 mRNA expression in caput epididymidis was unchanged compared with controls. However, in corpus and cauda epididymides as well as in vas deferens, the expression level of Hsp70-1 transcript was higher for the cryptorchid tissues. Changes in mRNA frequency were specifically correlated with the age of the patients. By opposition to the mRNA, western blot analysis revealed that Hsp70 protein levels were not affected by the inguinal location of the epididymis. The data show that Hsp70-1 transcript and protein were constitutively expressed in human excurrent duct and that an inguinal location can stimulate the expression of Hsp70-1 mRNA along the human epididymis and ductus deferens.

The effect of cryptorchidism on inhibin B in a subfertile population

Prepubertal cryptorchidism may cause fertility problems in adulthood, due to impaired spermatogenesis. Serum inhibin B has emerged as an accurate marker of spermatogenesis. The aim of this study was to evaluate the impact of a history of cryptorchidism on serum inhibin B levels and other markers of spermatogenesis in subfertile men. In a retrospective study, the effect of cryptorchidism on inhibin B, FSH, LH, free testosterone, testicular volume and semen parameters was assessed in a case-control study within a population of 2613 subfertile men. Of these, 161 and 102 subjects had a history of, respectively, unilateral and bilateral cryptorchidism that was treated by orchiopexy in childhood. Hormone data were complete for 64 cryptorchid patients (32 unilateral and 32 bilateral). A group of 128 patients was randomly selected out of the remaining group of 2350 men with idiopathic subfertility. An additional control group consisted of 32 fertile men from the general population. In cryptorchid subfertile men, inhibin B concentrations were significantly lower than in noncryptorchid subfertile men and fertile men (103 ng/l, 143 ng/l and 148 ng/l, respectively; P < 0.01). The FSH concentration was significantly higher in cryptorchid men vs. noncryptorchid men and controls (6.1 IU/l vs. 3.3 and 2.9 IU/l, respectively; P < 0.01). Testicular volumes and sperm concentration of cryptorchid men were significantly lower than in noncryptorchid subfertile men (12 vs. 15 ml, P < 0.01 and 3.8 x 10(6) sperm/ml vs. 17.4 x 10(6) sperm/ml; P < 0.05). A significantly higher inhibin B level and sperm concentration was observed in men undergoing orchiopexy at an early age (1-4 years) compared with men treated between 5 and 9 years or later (P < 0.05). Spermatogenesis is more impaired in cryptorchid subfertile men compared to men with idiopathic subfertility, as reflected by a lower inhibin B concentration.

Spermatogenesis in Azoospermic, Formerly Cryptorchid Men

To assess the use of testicular needle aspiration techniques to evaluate fertility potential in azoospermic, formerly cryptorchid men. Fifteen consecutive adult azoospermic, formerly cryptorchid patients (eight unilateral and seven bilateral) were examined by needle aspiration techniques, fine (FNA) and large needle (LNAB) testicular aspiration biopsy, for cytologic and histologic analysis. Five of the 15 subsequently underwent surgical biopsy for attempted assisted fertilization. Spermatozoa or spermatids were detected by FNA cytology or LNAB histology in one or both testicles in 87.5% of the unilateral and 28.6% of the bilaterally affected, formerly cryptorchid patients (P = .041, Fisher's exact test). The addition of LNAB to FNA identified spermatids in one patient with unilateral cryptorchidism and only Sertoli cells on FNA cytology. Furthermore, LNAB differentiated testicles with the cytologic finding of only Sertoli cells into those with or without diffuse fibrosis. In the five patients in whom assisted fertilization was attempted, the needle aspiration techniques predicted the presence or absence of spermatozoa in the subsequent surgical biopsy. The two needle aspiration techniques can be used to assess the fertility potential of azoospermic, formerly cryptorchid men and to select patients for assisted fertilization.

5α-reductase type 2 genes in Japanese males do not appear to be associated with cryptorchidism

Objective: To evaluate the occurrence of mutations of 5α-reductase type 2 gene in patients with cryptorchidism or idiopathic azoospermia. Design: Controlled clinical study. Setting: Yamagata University Hospital, Yamagata and Tokyo Electric Power Company Hospital, Tokyo, Japan. Patient(s): Patients with isolated cryptorchidism (n = 48) or idiopathic azoospermia (n = 33) and a control group of males with proven fertility (n = 51). Intervention(s): Collection and analysis of blood, leukocytic DNA, semen, and testicular biopsy. Main Outcome Measure(s): Semen analysis, screening of the 5α-reductase type 2 gene within exon 1 using direct sequencing and exons 2–5 using single strand conformational polymorphism analysis. Result(s): No mutations were detected in isolated cryptorchid men, idiopathic azoospermic men, or controls within the 5 exons of the 5α-reductase type 2 gene. Conclusion(s): 5α-Reductase type 2 gene abnormalities do not constitute a major factor in the development of cryptorchidism or idiopathic azoospermia.

Leydig Cell Function After Cryptorchidism: Evidence Of The Beneficial Result Of Early Surgery

We determined whether there are differences indicative of the function of the Leydig cell-pituitary axis in formerly unilateral cryptorchid men. Parameters were compared with those in control men. We determined luteinizing hormone, testosterone, free testosterone, follicle-stimulating hormone, inhibin B, sperm density, motility and morphology, testicular volume, patient weight and age at orchiopexy or at other nonrelated childhood surgery in controls. Significant correlations were noted between hormone levels and other parameters. An inverse correlation between age of surgery and testosterone suggested the detrimental effect of deferring orchiopexy during childhood. Correlations of testosterone with sperm density, motility and morphology suggested a direct relationship between spermatogenesis and testosterone in cryptorchid men. An inverse relationship between body weight and testosterone was observed in each group. There was considerable variation in the range of parameters, sometimes extending into the abnormal range. However, results indicated no differences in mean free testosterone, testosterone or luteinizing hormone in the formerly cryptorchid and control groups, and no difference in time to conception in fertile, formerly cryptorchid men and controls. Furthermore, there were no differences in hormone levels in fertile (as indicated by paternity) and infertile formerly cryptorchid men. This study suggests that men who underwent orchiopexy in later childhood have subclinically decreased Leydig cell function. It may result in a less than optimal hormonal milieu for adult reproductive function. These data provide support for orchiopexy during infancy to preserve Leydig cell function and, thereby, potentially enhance fertility.

Inhibin B: comparison with indexes of fertility among formerly cryptorchid and control men.

Infertility may be a consequence of cryptorchidism. We previously reported, using a large study cohort, that 38% of formerly bilateral cryptorchid men, 10% of unilateral cryptorchid men, and 5% of the control group were infertile. Men from this cohort donated blood and semen samples for inhibin B, FSH, LH, testosterone, free testosterone, and semen analyses. Results are reported comparing the entire group; some comparisons are based on normal or low sperm density. Data are also presented for men who had fathered children or had unsuccessfully attempted paternity. Mean (+/-SD) inhibin B levels were lower for the cryptorchid men (109 +/- 59 pg/mL) than the control men (153 +/- 60; P < 0.001), and FSH levels were higher (7.4 +/- 6.2 and 4.0 +/- 3.2; P < 0.0001). Inhibin B levels correlated with all other parameters for the cryptorchid group; however, correlations for the control group were only found with gonadotropins. Among the cryptorchid men, levels were significantly greater among men with normal sperm counts than men with low sperm counts (124 +/- 47 vs. 75 +/- 48 pg/mL; P < 0.0001). No difference was present for the control group (155 +/- 61 vs. 149 +/- 63 pg/mL). When the fertile group (based on paternity) vs. the infertile group (based on attempted paternity) were compared, significant differences were found for the cryptorchid group (117 +/- 62 vs. 73 +/- 52 pg/mL; P < 0.03), but not the control group (163 +/- 62 vs. 146 +/- 73 pg/mL). These data reveal relationships not apparent among the control group of men, which includes infertile men. Inhibin B data suggest that a larger portion of formerly cryptorchid men have compromised testicular function than indicated by paternity data. Low levels of inhibin B among individuals are an indication of diminished seminiferous tubule function and thus compromised potential for fertility. Low inhibin B levels together with elevated FSH levels and decreased sperm density are indicative of a high risk of infertility.

Inhibin B: Comparison with Indexes of Fertility among Formerly Cryptorchid and Control Men

Inhibin B: Comparison with Indexes of Fertility among Formerly Cryptorchid and Control Men

Fertility after Unilateral Cryptorchidism

Objective: To further evaluate whether fertility is decreased among a cohort of men with previous unilateral cryptorchidism as compared with a control group of men. Subjects and Methods: Formerly unilateral cryptorchid men who had undergone orchiopexy between the years of 1955 and 1975 at the Children’s Hospital of Pittsburgh and a control group of men who were matched for age of an unrelated surgery at the same institution were evaluated by review of medical records and by completion of a questionnaire. 359 previously cryptorchid men were identified as having attempted paternity. Of these men, 320 had information concerning preoperative testicular location and 163 for preoperative testicular size. 106 of these men had levels of testosterone, inhibin B, FSH, and LH measured, while 95 of the men had semen analyses. Results: Among men who had attempted paternity, there was no statistical difference in success of paternity between the previously unilateral group (89.7%) and the control group (93.7%). There was no difference in the mean time to conception (7.1 ± 0.7 months for the unilateral group vs. 6.9 ± 2.3 for the control group). Within the unilateral group in regard to success at paternity, no difference was found compared with the age of orchiopexy, preoperative testicular location, or preoperative testicular size. Inhibin B levels were lower among the unilateral group. FSH, LH, testosterone, sperm density, motility and morphology were not different, but considerable variation was noted within the cryptorchid group. Conclusions: In this continued evaluation of a cohort of previously cryptorchid men who had undergone unilateral orchiopexy, paternity does not appear to be significantly compromised after unilateral cryptorchidism. Unilateral cryptorchidism appears to be one of several factors contributing to infertility, similar to those found in the general population. No correlation was found between success at paternity and the age of orchiopexy, preoperative testicular size or preoperative testicular location. Inhibin B levels were lower while FSH, LH, T and sperm parameters did not differ.

Fertility after Bilateral Cryptorchidism

Purpose: Evaluation of the fertility of a cohort of formerly bilaterally cryptorchid men in comparison with a group of formerly unilaterally cryptorchid men, and a group of control men. Materials and Methods: Using a detailed questionnaire concerning paternity and factors related to paternity, a cohort of formerly bilateral cryptorchid men were studied and compared with men who had undergone orchiopexy for unilateral cryptorchidism, and a group of control men. All study subjects had had surgery at the Children’s Hospital of Pittsburgh, Pittsburgh, Pa., between 1955 and 1975. A subset of the full cohort underwent clinical evaluation that included a physical examination, serum hormonal determination and semen analyses. Results: Paternity rates are significantly lower among the formerly bilaterally cryptorchid men who have attempted to father a child (65.3%) as compared to the formerly unilaterally cryptorchid (89.7%; p < 0.001) and control men (93.2%; p < 0.001). Differences in the ability to father children are also apparent when semen and hormone levels are compared between the three groups. The bilateral group has significantly lower sperm density and inhibin B levels, and higher FSH and LH levels, than the unilateral and control groups. Conclusions: Men born with bilateral cryptorchidism have severely compromised fertility in adulthood. This reduction in fertility is clearly shown in comparisons of both paternity rates, and in semen and hormone analyses, between the formerly bilateral, formerly unilateral, and control groups.

Correlation between testicular biopsies (prepubertal and postpubertal) and spermiogram in cryptorchid men

Twenty-one young men who underwent testicular biopsy and orchidopexy in infancy consulted owing to infertility and had biopsies again. The first and second biopsy specimens from these patients were compared by means of a semiquantitative study of the seminiferous tubules to evaluate the evolution of germ cells and to correlate these data with spermatozoon numbers. The infant testes showing lesions were classified into 3 types according to the mean tubular diameter and tubular fertility index: (1) slight lesions, (2) marked germinal hypoplasia, and (3) severe germinal hypoplasia. In the adult testes, spermatogenesis was evaluated by calculating the average numbers of spermatogonia, primary spermatocytes, young spermatids, and mature spermatids. These testes were classified as (1) normal; (2) having lesions in the adluminal compartment; (3) having lesions in the basal compartment; and (4) mixed atrophy. The number of differentiated spermatids was correlated with the expected number of spermatozoa in the ejaculate by a power regression curve. The observation of certain histologic lesions in the seminiferous tubules was assumed to indicate excretory duct obstruction: ectasia, indented outline of the seminiferous epithelium, intratesticular spermatocele, apical cytoplasmic vacuolation of Sertoli cells, and mosaic distribution of testicular lesions. There was a correlation between the prepubertal lesions and the degree of spermatogenesis in postpubertal biopsy specimens. The evolution of the 40 testes without regard to their location in infancy (cryptorchid or scrotal) was as follows. The 14 infant testes with a normal histologic pattern (5 testes) or minor lesions (9 testes) evolved to testes with lesions of the adluminal compartment (8 testes), mixed atrophy (4 testes), or lesions of the basal and adluminal compartments (2 testes). The 6 testes with marked germinal hypoplasia evolved to testes with mixed atrophy. The 20 testes with severe germinal hypoplasia evolved to testes with mixed atrophy (17 testes), Sertoli-cell-only tubules (2 testes), or lesions in the basal compartment (1 testis). In the 9 patients with a histologic pattern of obstruction bilaterally (6 men) or unilaterally (3 men), the expected number of spermatozoa according to the correlation curve was much higher than the actual number in the spermiogram. This means that the testes of many azoospermic men produce spermatozoa, and this finding corroborates the importance of testicular biopsy in infertility studies. H UM P ATHOL 31:1022-1030.