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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 6 2414-2419
Copyright © 2001 by The Endocrine Society

Original Articles: Hormones and Reproductive Health

Sertoli Cell Function in Infertile Patients with and without Microdeletions of the Azoospermia Factors on the Y Chromosome Long Arm1

Carlo Foresta, Andrea Bettella, Enrico Moro, Alberto Roverato, Maurizio Merico and Alberto Ferlin

Department of Medical and Surgical Sciences (C.F., A.B., E.M., M.M., A.F.), University of Padova, 35128 Padova, Italy; and Department of Political Economy (A.R.), Statistical Unit, University of Modena and Reggio Emilia, 41100 Modena, Italy

Address all correspondence and requests for reprints to: Prof. Carlo Foresta, M.D., Department of Medical and Surgical Sciences, University of Padova, Clinica Medica 3, Via Ospedale 105, 35128 Padova, Italy. E-mail: forestac{at}protec.it

Abstract

Deletions of the azoospermia factors on the Y chromosome long arm are an important cause of male infertility, and they may involve germ cell-specific genes or ubiquitously expressed genes. To date, no clinical or hormonal parameters have yet been found to distinguish patients with and without Yq microdeletions. In particular, Sertoli cell function, as evaluated by inhibin B, has not yet been described. Our hypothesis was that microdeletions involving genes specifically expressed in germ cells should not alter Sertoli cell function. To do this, we have evaluated the testicular hormonal function in infertile patients affected by severe testiculopathies with and without Yq microdeletions, with particular emphasis on Sertoli cell function. We studied 102 well-characterized infertile patients; 27 had Yq microdeletions, and 75 were classified as idiopathic infertiles. Patients with Yq microdeletions had lower FSH and higher inhibin B plasma concentrations with respect to patients without microdeletions, suggesting that Sertoli cell function in Yq-deleted men is only partially altered. Furthermore, patients with deletions involving germ cell-specific genes had higher concentrations of inhibin B with respect to patients with deletions of ubiquitously expressed genes. These results suggested that a specific alteration of germ cells only partially influences Sertoli cell function. Hormonal status of patients without deletions suggested that in such cases the cause that has determined the spermatogenic defect may have damaged both Sertoli and germ cells. Inhibin B production in patients with Yq deletions was about 70% higher than the nondeleted patients, and the functional relationship between FSH and inhibin B was normally preserved. This study elucidated the multifactorial mechanisms underlying spermatogenic defects, where Sertoli cells may be normally functioning or damaged depending on the primary cause that has determined the testicular damage.

RECENTLY, VARIOUS STUDIES described a possible role of the Y chromosome long arm (Yq) in the regulation of spermatogenesis and in the pathogenesis of idiopathic male infertility. This research showed that Yq microdeletions are responsible for 10–15% of idiopathic severe oligozoospermia and azoospermia (for review see Ref. 1). Three distinct regions, designed azoospermia factor (AZF) a, b, and c, from proximal to distal Yq are required for normal spermatogenesis (2), and deletions detected in infertile males most frequently occur in the AZFc region. The deleted in azoospermia (DAZ) gene is a multicopy gene specifically expressed in male germ cells (3, 4), and it is considered the responsible for the AZFc phenotype (3). The candidate gene for the AZFb region is RNA-binding motif on the Y (RBMY), which is again a multicopy gene with germ cell-specific expression (5). Candidate genes for AZFa include ubiquitin-specific protease 9, Y chromosome (USP9Y; previously known as DFFRY, Drosophila fat-facets related on the Y) (6, 7) and DEAD-box on the Y (DBY) (8). These genes differ from DAZ and RBMY because they are in single copy and show ubiquitous expression, even if DBY has testis-specific transcripts (8, 9). However, the specific testicular cells (germ cells, Sertoli cells, interstitial cells) in which AZFa genes are expressed is still unknown.

The phenotypes associated with deletions in the different AZF regions are variable, and, in general, there is no clear relation between genotype and testicular phenotype (1, 10, 11). Spermatogenic alterations may vary from severe hypospermatogenesis to Sertoli cell only (SCO) and to spermatogenic arrest. The only finding that seems sufficiently clear is that large deletions involving more than one AZF locus are invariably associated with a more severe tubular damage. In fact, in patients with deletions of AZFa+b+c intervals a SCO syndrome (SCOS) is always observed (1). Also, the clinical presentation of patients with Yq microdeletions is variable: it includes subjects with azoospermia, small testes, and high FSH plasma concentrations as well as subjects with oligozoospermia and normal or only slightly elevated FSH levels (10, 12). Furthermore, no clinical or hormonal parameter have yet been found to distinguish infertile patients affected by severe testiculopathies with and without Yq microdeletions (1).

Sertoli cell function, as evaluated by inhibin B plasma concentrations, has not yet been described in patients with Yq microdeletions. Indeed, such patients represent an interesting in vivo experimental model to study the relation between Sertoli cell function and its control by spermatogenic cells. In fact, if microdeletions involve genes specifically expressed in germ cells (such as DAZ and RMBY), Sertoli cell function itself should theoretically be normal. Therefore, the influence of germ cells on Sertoli cells should be evident. On the contrary, in other testiculopathies caused by well known aetiologies, such as cryptorchidism, varicocele, orchitis, etc., the cause determining the damage of the spermatogenic process could also alter the Sertoli cells.

In this study, we have evaluated the testicular hormonal function in infertile patients affected by severe testiculopathies with and without Yq microdeletions, with particular emphasis to Sertoli cell function, as evaluated by inhibin B plasma concentrations.

Materials and Methods

The study was approved by the Hospital Ethical Committee, and informed consent was obtained from each subject.

Semen analysis, bilateral fine-needle aspiration cytology (13), and PCR analysis of Yq euchromatin using 40 sequence tagged sites (STSs) (8, 12) allowed us to select 102 well-characterized infertile patients who satisfied the following criteria: 1) they were affected either by azoospermia or severe oligozoospermia (sperm count <5 x 106/mL) with a testicular cytological picture of SCOS or severe hypospermatogenesis, respectively; 2) they showed either Yq microdeletions as the only cause of the spermatogenic alteration (27 patients) or were classified as idiopathic infertiles (no Yq microdeletions or other apparent aetiologies, such as cryptorchidism, varicocele, testicular trauma, endocrinopathies, etc.) (75 patients). Semen samples were obtained on 2 different occasions, separated by a 3-week interval with 3 days of sexual abstinence, and they were examined following WHO guidelines (14). Azoospermia was confirmed by centrifugation. Fifty age-matched normozoospermic subjects were considered as controls.

All subjects carried a normal 46,XY karyotype and PCR analysis of Yq was performed as previously described (8, 12). Negative results (no amplification) were considered only after three amplification failures, eventually repeating the experiments on new DNA extracted from a second blood collection, in the presence of the other Yq STSs and confirmed by the coamplification of the SRY gene (sY14) (15), as previously reported (8, 12). Confirmation of deletions was eventually performed by Southern blotting (12, 16, 17).

Details of the testicular fine-needle aspiration technique and analysis have been given previously (13, 18, 19). Briefly, SCOS is characterized by the complete absence of spermatogenic cells in both testes, whereas severe hypospermatogenesis shows a strong quantitative reduction in the absolute number of these cells; however, the cells are in normal relative proportions, i.e. no maturation disturbances are present.

FSH and LH plasma concentrations were measured in each subject by RIA using 125I-labeled FSH and LH (Ares-Serono, Milan, Italy). Intraassay and interassay coefficients of variation were 2.6 and 3.6%, and 3.7 and 2.8%, respectively. Testosterone was measured using the double antibody RIA using commercial kits (Radim, Rome, Italy). Intraassay and interassay coefficients of variation were 7.8 and 7.0%, respectively. Estradiol was measured by RIA using commercial kits (Radim). Intraassay and interassay coefficients of varation were 7.5 and 9.8%, respectively. Plasma levels of inhibin B were measured by a solid-phase sandwich enzyme-linked immunosorbent assay specific for the dimeric inhibin-B form (Serotec, Oxford, UK) (20, 21). The first antibody is directed to the ßB-subunit and the second antibody to the {alpha}-subunit and conjugated to alkaline phosphatase. The assay has less than 0.1% cross-reactivity with activin forms and approximately 1% with inhibin A. Assay sensitivity was 15 pg/mL and the interplate and intraplate variation coefficients were 6.4% and 6.8%, respectively.

Statistical analysis was performed with the S-Plus statistical package (22) and using linear regression and ANOVA. The results are given as mean ± SD. P values less than 0.05 and 0.01 were regarded as statistically significant and highly significant, respectively.

Results

Figure 1Go shows the STS-PCR data of the 27 infertile patients with Yq deletions as follows: 14 patients had deletions that overlap the AZFc interval including the DAZ gene cluster (subintervals 6C-E); 8 patients had complete deletions of AZFb and AZFc regions removing both RBMY and DAZ genes (subintervals 5O-6E); 3 patients had a deletion in AZFa, one of which with absence of USP9Y and DBY genes and two with absence of DBY only; in the other 2 patients the deletion involved a large portion of the Y chromosome including AZFa, b, and c (subintervals 5C-6E), therefore, removing USP9Y, DBY, UTY, RBMY and DAZ genes.



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  		Figure 1. Schematic representation of the Yq microdeletion pattern in the 27 patients considered for this study. At the top, the long arm of the Y chromosome (centromere at left) is represented, with indication of the AZF regions and the candidate genes. Deletion breakpoints are shown below; filled black bars denote the presence and white bars the absence (deletion) of the corresponding DNA sequences.

 
Semen parameters, testicular volumes and cytology, LH, testosterone and estradiol plasma levels were not different in the two groups of infertile patients considered for this study, i.e. patients with idiopathic testiculopathy and patients with Yq microdeletions (data not shown). On the contrary, differences were found for FSH and inhibin B plasma levels, and these data are summarized in Table 1Go. FSH values of both groups of patients were higher than controls (P < 0.001). They were apparently higher in patients without deletions (19.1 ± 14.1 IU/L) with respect to patients with Yq deletions (11.9 ± 6.5 IU/L), but this difference did not reach statistical significance. Inhibin B plasma levels were reduced in both groups of infertile patients with respect to control subjects (P < 0.001), and they were significantly different in patients with deletions with respect to patients without deletions (152.2 ± 59.4 pg/mL vs. 76.5 ± 46.1 pg/mL, P < 0.001). In Table 2Go, FSH and inhibin B data are showed with respect to the testicular phenotype (SCOS or severe hypospermatogenesis) and distinguishing patients with and without Yq deletions. Patients with SCOS and Yq deletions had FSH values lower than SCOS patients without deletions (15.8 ± 10.9 vs. 30.8 ± 12.7 IU/L, P < 0.05), and this behavior was observed also in patients with severe hypospermatogenesis (7.8 ± 3.4 vs. 12.9 ± 10.4 IU/L, P < 0.05). Similarly, inhibin B levels in patients with deletions were higher than in patients without deletions, both in the presence of SCOS (121.5 ± 75.2 vs. 50.6 ± 37.5 pg/mL, P < 0.05) and of severe hypospermatogenesis (185.2 ± 69.1 vs. 90.3 ± 44.6 pg/mL, P < 0.001). Each group of patients showed higher FSH levels than controls; inhibin B levels were significantly reduced in all patients without Yq deletions with respect to normozoospermic subjects, whereas there was no significant difference between controls and patients with deletions, even if mean values were lower in this group of patients (121.5 ± 75.2 in SCOS patients and 185.2 ± 69.1 pg/mL in severe hypospermatogenesis). Table 3Go shows FSH and inhibin B levels in patients with Yq deletions classified on the basis of the localization of the deletion. We did not find significant differences in FSH levels with respect to patients without deletions, and this is probably due to the low number of patients in each group. Inhibin B levels were significantly higher in patients with deletions of AZFc or AZFb+c with respect to nondeleted patients (163.8 ± 45.3 and 168.4 ± 47.5 pg/mL, respectively, vs. 76.5 ± 46.1); comparisons were not possible for the other groups due to the low number of patients.


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  		Table 1. FSH and inhibin B plasma concentrations in patients with and without Yq deletions, compared with control subjects

 

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  		Table 2. FSH and inhibin B plasma concentrations in patients with and without Yq deletions classified on the basis of their testicular cytological picture, compared with control subjects

 

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  		Table 3. FSH and inhibin B plasma concentrations in patients with Yq deletions classified on the basis of the localization of the deletion, in patients without deletions, and in control subjects

 
The functional relation between FSH and inhibin B was first analyzed independently in the three groups (normal subjects, patients with Yq microdeletions, and patients without Yq microdeletions) by fitting three separate regressions. In the normal subjects there was strong evidence for a negative correlation between FSH and inhibin B (Fig. 2aGo). However, it is important to point out that the regression line is estimated with low precision because the 95% confidence intervals of the regression coefficients are very wide (238.60; 339.22 and -5.09; -38.18). In patients with Yq deletions there was a negative correlation between FSH and inhibin B (Fig. 2bGo). For this group of patients the data allowed a more accurate estimate of the regression line because the estimated slope is -5.6 and the 95% confidence interval (-2.56; -8.58) is considerably narrower than the previous case. In patients without deletions there is clear evidence of nonlinear relation between FSH and inhibin B. In fact, a quadratic regression provides an adequate fit of the data (Fig. 2cGo), and the estimated curve shows a decreasing behavior for FSH values lower than 34 IU/L and an increasing behavior for higher values of FSH. Also, in this case, the precision of the estimates is satisfactory.



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  		Figure 2. Relation between FSH and inhibin B plasma concentrations in the control subjects (A), patients with Yq deletions (B), and patients without Yq deletions (C). In the latter group both the nonlinear relation obtained considering all the FSH values (statistical data at right) and the linear relation obtained considering only FSH values less than 30 IU/L (statistical data at left) are shown (see Results).

 
Then, we compared the FSH-inhibin B relation for the three groups. It should be noted that for both the normozoospermic subjects and the patients with Yq deletions all the observed FSH values are lower than 30 IU/L and that in this interval the fitted quadratic regression for patients without Yq deletions is nearly linear (Fig. 2cGo). For this reason, we carried out the comparison only on the common range of observed values; that is for FSH smaller than 30 IU/L. The most intriguing data result from the comparison between the regression lines of patients with and without Yq deletions (Fig. 3Go). In this case the P value was less than 0.001, indicating that the difference between the regression lines is highly significant. An informal analysis shows that Yq-deleted patients are characterized by higher values of inhibin B but the difference decreases as FSH increases (Fig. 3aGo). This finding suggested that the different behavior between the two groups of patients might well be described in terms of proportionality. More precisely, the difference between the two groups of patients is no longer significant if inhibin B values of patients without deletions are multiplied by a constant C. A formal statistical test with asymptotic normal distribution estimated the value of C in 1.713. This result implies that inhibin B production in Yq-deleted patients is 71.3% higher than nondeleted patients. In Fig. 3bGo a visual representation of this result is given; when inhibin B values of patients without deletions are multiplied by 1.713 and compared with deleted patients the two regression lines are nearly identical, confirming our hypothesis.



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  		Figure 3. Comparison of the FSH-inhibin B relation between patients with and without Yq deletions. A, Regression lines resulting from analysis of the data for FSH values less than 30 IU/L. B, Regression lines as they result from the same set of data after multiplication of inhibin B values of nondeleted patients by a constant C of 1.713 (see text).

 
Discussion

Sertoli cells are essential in the mechanisms triggering and regulating the process of spermatogenesis, and it is generally assumed that disruption of their function may be expressed by a reduction in the production of their specific protein inhibin B (for review see Ref. 23). The principal role of inhibin B is to act as a long loop feedback system controlling FSH secretion, and recent studies performed with assays specific for inhibin A and B (20) have shown a negative correlation between FSH and inhibin B levels, both in normal subjects and in men with severe testicular damage (24, 25). The production of inhibin B by Sertoli cells reflects interactions between these and neighboring germ cells (26). Therefore, the reduction of inhibin B concentrations is considered a marker of the functional state of the seminiferous epithelium instead of a marker only of specific alteration of the Sertoli cells, even if many causes damaging germ cells could directly alter Sertoli cells, too. In infertile patients affected by Yq microdeletions, above all when the deletion removes genes codifying proteins expressed exclusively in the germ cells (such as DAZ and RBMY), spermatogenesis is defective because of intrinsic germ cell abnormalities, and Sertoli cells should not be directly affected. In these patients, Sertoli cell function should be altered only by anomalous interrelations with germ cells, that are reduced in number or completely absent. On the contrary, it can be speculated that large deletions of Yq or microdeletions specifically removing the ubiquitously expressed AZFa-genes may directly alter both germ and Sertoli cells.

The findings obtained in this study showed that infertile patients with Yq microdeletions have higher FSH plasma levels than controls, but they seem to be lower with respect to patients affected by similar testicular damage but without Yq microdeletions. This hypothesis is supported by inhibin B concentrations, which were significantly higher in patients with deletions. These data suggest that the Sertoli cell function in Yq-deleted patients is only partially altered, and in particular they demonstrate that the production of inhibin B may be maintained independently from neighboring germ cells. This is supported also by the evidence that patients with deletions involving germ cell-specific genes, such as those limited to AZFc (removing DAZ), AZFb+c (removing RBMY and DAZ) or DBY, showed the highest concentrations of inhibin B, whereas this hormone was strongly reduced in patients with larger deletions involving also ubiquitously expressed genes. On the contrary, patients without Yq microdeletions invariably had lower inhibin B concentrations, suggesting that in such cases the cause that has determined the spermatogenic defect may have damaged both Sertoli and germ cells. Although the influence of testosterone and estradiol could not be excluded, plasma concentrations of these hormones were not different from control subjects and between the two groups of patients. Therefore, the role of sex steroids in controlling gonadotropin secretion is still unclear.

The preservation of a relation between FSH and inhibin B plasma levels in Yq-deleted patients clearly demonstrated that pituitary sensitivity to inhibin B negative feedback is not altered. The most intriguing data obtained in this study came from the comparison of this relation between patients with and without Yq deletions. This analysis evidenced that inhibin B production in deleted patients was about 70% higher than the nondeleted patients. There may be two possibilities to explain these results. The relative contribution of germ cells to inhibin B production is about 30%. In this case a further reduction in inhibin B production should reflect an additional intrinsic alteration of Sertoli cells. Or other intratesticular mechanisms regulating Sertoli cell function may be involved. In fact, inhibin B production by Sertoli cells may also be influenced by Leydig cell function, because there are intercellular communications between the Leydig-Sertoli-germ cell compartments. Therefore, in patients without Yq microdeletions such mechanisms should be altered, whereas they should be normally functional in Yq-deleted patients.

The results of our study suggested that the involvement of Sertoli cells in determining spermatogenic impairment might be different in various kinds of testiculopathies. An alteration in the functional activity of these cells may contribute to further increase a spermatogenic failure initially caused only by germ cell disruption. This hypothesis well agrees with the recent results obtained by Bar-Shira Maymon et al. (27), who demonstrated that cytokeratin-18, a marker for Sertoli cell dysfunction, is strongly expressed in Sertoli cells from subjects affected by severe testiculopathies without Yq microdeletions, whereas it is completely normal in patients with Yq microdeletions.

This study elucidated the multifactorial mechanism underlying spermatogenic defects in humans, by analyzing an important and unique model, such as that represented by patients with microdeletions in Yq. We showed that the spermatogenic alteration associated with lack of germ cell-specific genes results from a primary defect intrinsic to germ cells whereas Sertoli cells are not affected. On the contrary, other testiculopathies may be associated with dysfunction also of the Sertoli cells, and probably in these cases the primary alteration was a combined damage to both Sertoli and germ cells. Plasma concentrations of FSH were not significantly different between patients with and without microdeletions of the Y chromosome and, therefore, they seem inadequate to identify patients at risk for microdeletions. However, we believe that an increase in patient number would clarify this aspect, because we observed a trend characterized by lower FSH levels in deleted patients than nondeleted patients. Inhibin B plasma levels clearly distinguish the two groups of patients. Therefore, the inclusion of the measurement of this hormone in the diagnostic workup allows a better management of the infertile man.

Footnotes

1 The financial support of Telethon-Italy (Grant E.C0988) is gratefully acknowledged. Back

Received December 8, 2000.

Revised January 26, 2001.

Accepted February 14, 2001.

References

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