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Original Articles: Hormones and Reproductive Health |
Institute of Reproductive Medicine, University of Münster, D-48129 Münster, Germany
Address all correspondence and requests for reprints to: Prof. Dr. E. Nieschlag, F.R.C.P., Institute of Reproductive Medicine, University of Münster, Domagkstrasse 11, D-48129 Münster, Germany. E-mail: nieschl{at}uni-muenster.de
Abstract
Androgens are essential for the maintenance of normal spermatogenesis. Androgen action is mediated by the androgen receptor (AR), which in the testis is expressed by Leydig, peritubular, and Sertoli cells. The fact that sperm numbers range from 20 up to 300 million/mL in normal men without any indication of changed endocrine parameters led us to assume that genetic variability of transduction of androgen signaling could be important. We therefore compared the variable number of CAG repeats in the AR with sperm concentrations in men with normal ejaculate parameters (62 fathers and 69 volunteers participating in clinical trials). In multivariate analysis CAG repeat length did not differ between the volunteers (19.4 ± 3.1) and the fathers (20.6 ± 3.0), but was significantly correlated to sperm concentrations with a coefficient of -0.25. When compared with a group of infertile men with (n = 14) or without (n = 30) a family history of infertility, no such correlation was found. These results indicate that men with short CAG repeats have the highest sperm output within the normal fertile population. Polymorphisms of the AR contribute to the efficiency of spermatogenesis in normal men, but do not play a predominant role in male infertility.
WITH INCREASING knowledge of the human genome it becomes evident that genetic variations or polymorphisms are frequent in hormones and receptors that belong to the endocrine system of reproduction. The incidence of such polymorphisms within a given gene ranges from 15–50% among the normal population. This indicates that these genetic changes do not have any gross effect on reproduction; otherwise, evolution would have exerted deleterious effects on polymorphisms, but it is likely that they are capable of modifying or fine-tuning endocrine feedback systems and hormone action.
Testosterone is critically involved in the initiation and maintenance of spermatogenesis (1), and impaired androgen signaling caused by mutations has been shown to be involved in some forms of male infertility (2). Thus, changes in the biochemical properties of the androgen receptor (AR), such as subtle genetic variations, could affect sperm production by modulating androgen signaling. The AR is encoded by a gene located on the X chromosome at Xq 11–12 (3, 4). The receptor exhibits a polymorphic site in exon 1, which is characterized by different numbers of CAG repeats resulting in variable lengths of a common polyglutamine stretch. In healthy populations the number of CAG repeats ranges from 11–31. Expansions of more than 40 repeats occur in neurodegenerative diseases, which are also characterized by signs of partial androgen deficiency. Although the pathogenic mechanisms are not fully elucidated, in vitro data suggest that the number of triplets affects the interaction with corresponding cofactors and thereby the trans-activation of the receptor (5, 6). A recent study suggested an association between idiopathic infertility and an extended number of CAG repeats in the AR (7). However, confirmation of this observation failed in other studies (8, 9, 10).
Following our hypothesis on the impact of genetic variants of the AR on sperm production among normal men, we investigated the number of CAG repeats in a group of men with normal results of semen analysis according to WHO criteria and a group of proven fathers with known ejaculate parameters. In addition, men with idiopathic oligo- or azoospermia, who either had a negative or a positive family history for male infertility, were investigated.
Subjects and Methods
Subjects
In a retrospective analysis we studied 131 controls (groups I and II) and 43 patients (groups III and IV). Group I encompassed 69 men who had participated in different studies on hormonal male contraception (11, 12, 13) and had not fathered children to date. As an inclusion criterion for the study 2 semen samples with normal sperm count and motility as defined by WHO (14) were required. As a second control group (II) we analyzed 41 men who had fathered at least 1 child within the past year (15) and combined them with 21 proven fathers participating in contraceptive studies. Forty-three patients were included who had consulted our institute for infertility. Patients were identified according to 2 criteria: 1) men with idiopathic azoospermia and no other reported cases of infertility in their family (group III; n = 29); and 2) patients with idiopathic severe oligo- or azoospermia and a positive family history for infertility (group IV; n = 14). Family history was defined as positive if the patient reported having at least 1 brother who was also affected by male infertility or 1 male relative descending from his mother’s family. In all patients known genetic causes of infertility, such as abnormal karyotype, Y chromosomal microdeletions, Kallmann syndrome, or mutations in the cystic fibrosis transmembrane regulator gene had been excluded upon routine clinical work-up. The ethics committee of the Medical Faculty and the State Medical Board agreed to these investigations, and patients and volunteers gave informed consent.
Hormone analysis
Serum concentrations of FSH, LH, and sex hormone-binding globulin (SHBG) were analyzed by immunofluorometric assays (Autodelfia, Wallac, Inc., Freiburg, Germany). The lower detection limits were 0.12 and 0.25 IU/L for FSH and LH, respectively. The normal ranges are 1–7 and 2–10 IU/L for FSH and LH. The normal range for SHBG is 11–71 nmol/L. Serum testosterone was measured by RIA (Diagnostics Systems Laboratories, Inc., Sinsheim, Germany). The lower limit of normal is 12 nmol/L. Mean intra- and interassay coefficients of variation for all assays were below 3% and 7%, respectively. Free testosterone was calculated using the formula suggested by Vermeulen et al. (16). The androgen insensitivity index (ASI) was determined as the product of LH and testosterone (2). Inhibin B was measured using a commercially available double antibody, enzyme-linked immunoassay (Serotec, Oxford, UK). The sensitivity was 7.8 pg/mL. For patients and controls the mean of the first two hormone analyses performed in our laboratory was calculated and used for further statistical analysis.
Testicular volume
Determination of testicular volume was performed by sonography using a 7.5-MHz sector scan (Panther, B&K Medical, Gentofte, Denmark). The procedure for calculation of testicular volume has been described previously (17).
Semen analysis
Ejaculate analysis was performed according to WHO guidelines (14). Patients and volunteers were asked to abstain from sexual activity for 48 h to 7 days before the investigation. In cases of extremely low sperm count or suspected azoospermia, ejaculates were centrifuged, and sediments were analyzed. For patients and controls the mean of the first two ejaculates evaluated in our laboratory was calculated and used for further statistical analysis. Coefficients of variation for intraindividual differences in sperm concentrations showed a skewed distribution with a median of 0.19 and 5th to 95th percentiles of 0.02 and 0.7, respectively.
Determination of the CAG repeat number within exon 1 of the AR gene
DNA was isolated from blood samples using the Nucleon Kit (Amersham Pharmacia Biotech, Freiburg, Germany). A fragment of exon 1 of the AR was amplified by PCR. Each reaction sample (25 µL) contained 100–500 ng genomic DNA, 20 pmol AR exon 1 forward primer (5'-GCCTGTTGAACTCTTCTGAGC-3'), 20 pmol AR exon 1 reverse primer (5'-CGATGGGCTTGGGGAGAACCATCCTCA-3' IRD-800 labeled), reaction buffer [10 nmol/L Tris-HCl (pH 8.3), 50 nmol/L KCl, 0.01% gelatin, 2 nmol/L MgCl2, and 0.2 mmol/L deoxy-NTPs], and 2 U Taq polymerase (Promega Corp., Heidelberg, Germany). Thermal cycling parameters consist of a denaturing step at 94 C for 50 s, followed by the annealing step at 58 C for 40 s and an extension step at 72 C for 1 min. The number of cycles used for the amplification of exon 1 of the AR was 35, and the cycle program was preceded by incubation at 94 C for 2 min and was followed by a final extension step at 72 C for 10 min. The reliability of PCR was determined by 2% agarose gel electrophoresis.
The fluorescent PCR products (1–2 µL) were diluted with 2 µL loading dye sample (Amersham Pharmacia Biotech), and the total volume was adjusted to 5 µL using aqua dest. The samples were heated to 70 C for 1 min, then chilled on ice, and 1–2 µL were loaded onto a 6% denaturing sequencing gel. Samples were electrophoresed (Licor 4200) at 1500 V for 8 h.
The number of CAG repeats was calculated by comparing the detected PCR fragment to sequencing reactions that were run in parallel to the samples and served as molecular size markers. In addition, PCR samples with known numbers of CAG repeats (15, 20, and 30 CAG repeats, as determined by cloning and sequencing the corresponding AR exon 1 fragments) were used as internal standards for the calculation. By this, migration aberrations due to changes in the electrophoretic properties, which could result in incorrect repeat calculations, were excluded. Determination of CAG number was repeated twice on two separate gel runs. Some of the samples were cloned and sequenced to confirm the validity of the measurement method being used.
Statistics
Statistical analysis was performed using the statistical package SPSS for Windows (version 9.0, SPSS, Inc., Chicago, IL). All variables were checked for normal distribution by Kolmogorov-Smirnov one-sample test for goodness of fit. Descriptive statistics are given as either the mean ± SD or the median and 5th to 95th percentiles. For comparison between two groups one-way ANOVA was used, followed by Dunnett’s post-hoc test for intergroup comparison if an overall level of significance of P < 0.05 was reached. Comparison of distributions was performed by Kruskal-Wallis test. Pearson’s coefficient of correlation was used for bivariate regression analysis. Power analysis confirmed that the group size, including all normal men, was sufficient with 0.8. Because of interdependencies between single variables, stepwise multiple regression analysis was used to determine the impacts of different parameters on results of ejaculate analysis.
Results
Analysis of demographic, hormonal, and ejaculate data from fertile
men, the volunteers of contraceptive studies, and patients did not
reveal any significant differences among the groups. Only age was
significantly less in men taking part in contraceptive studies (Table 1
).
|
). Group
III differed significantly with respect to total testosterone and LH
levels from all other groups. Differences in testosterone levels
disappeared after correction for SHBG levels. The product of LH and
testosterone (ASI) was comparable in all groups. Except for 5 men, ASI
was in the normal range. An ASI of more than 200, which was previously
suggested to be a sensitive threshold for detection of AR mutations in
male infertility (18), was present in 2 men participating
in contraceptive trials, 1 father, and 2 patients within group III.
According to the Kruskal-Wallis test, distribution of CAG repeats was
statistically comparable between groups (Fig. 1). Although not statistically
significant, distribution had a slight shift to extreme values in the
lower part of the distribution in controls. Men with fewer than 15 CAG
repeats were never seen in our group of infertile men, whereas they
represented 1.4% of men in the contraceptive studies and 6.5% of the
fathers (Fig. 1).
|
).
Coefficients of correlation just failed to reach the border of
statistical significance in the group of fathers. As sperm
concentrations were below the lower limit of normal in 9.3% of fathers
(n = 4), correlation analysis was repeated for those 127 men with
normal sperm concentrations in both examinations. Correlation
coefficients reached the level of significance for total sperm count,
sperm concentrations, and LH (Table 3).
If the men were grouped into quintiles of CAG repeat length, ANOVA
revealed an overall statistical significance of P <
0,05 for sperm concentration. As shown in Fig. 2, mean sperm concentrations were
significantly higher in the post-hoc test in those men with
CAG repeats in the lower quintile of the overall distribution (<18)
than in men in the highest quintile (<23).
|
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|
). Discussion
Various lines of evidence from animal models as well as from clinical observations suggest that testosterone and FSH act synergistically on the maintenance and initiation of spermatogenesis (1). Our study confirms the previously reported relationship between serum FSH and sperm concentrations in the normal range (19). The mechanisms by which androgens regulate the spermatogenic process are not completely understood. The AR is expressed in Leydig as well as in peritubular and Sertoli cells of the human testis (20), providing sites for regulation of spermatogenesis and sperm outlet. Additionally, ARs can be found in epithelial and stromal cells of the epididymis, the efferent duct, and the seminal vesicles (21), which is compatible with the critical role of androgens in the epididymal secretory capacity.
Patients with partial androgen insensitivity caused by AR mutations characteristically exhibit elevated LH levels (5) in response to the impaired feedback signal of testosterone in the pituitary. The similar pattern we observed in normal men with a positive correlation between ASI and polyglutamine tracts suggests that a high number of CAG repeats is equivalent to a slightly reduced receptor activity, which, however, is sufficient to maintain normal testosterone action. However, the absent correlation between CAG length and testosterone itself is difficult to interpret. Leydig cell androgen secretion is mainly regulated via LH receptor-mediated events and, at least in experimental settings, a receptor down-regulation occurs in the presence of elevated LH levels (22).
Evidence for an inverse correlation between AR activity and the number of CAG repeats is provided by clinical findings and molecular studies. Patients with neurodegenerative disorders associated with more than 40 repeats, such as Kennedy disease, present with impaired virilization and reduced sperm counts (23). Epidemiologically, shorter CAG repeats are linked to an increased risk of prostate cancer (24). In vitro, short AR CAG alleles are associated with high intrinsic AR activity in reporter gene assays (25). Molecular mechanisms are not fully understood, but some possibilities, such as differences in the trans-activation activity of the receptor (26) or modulation of the cytoplasmatic transport rates of the receptor to the nucleus (27), have been put forward. Recently, it has been shown that expanded polyglutamine stretches bind preferentially to a coactivator regulating the cAMP response element-binding protein-dependent transcriptional activation (6).
This study provides evidence that a common polymorphism as an inherited characteristic of the AR is correlated to normal sperm output, whereas no association between male infertility and the number of CAG repeats in the AR was found. From these observations, interesting aspects arise concerning the physiological role of AR traits for the regulation of human spermatogenesis.
CAG repeat length varies significantly between ethnic groups, with the highest prevalence of short CAG repeats seen among African Americans and the longest among Asian men (28). The distribution of CAG repeats observed in our control population is comparable to that previously reported in fertile white men (7, 8). Interestingly, ethnic differences have been described for the spermatogenic capacity of the testis. Asian men have smaller testicular volumes and lower daily sperm production rates than Caucasians (29), but the physiological background remains unclear. The correlation between genetic traits of the AR and sperm concentration that we find in normal Caucasian men raises the question of whether ethnic differences in spermatogenesis may in part be explained by variations in testosterone action in the testis mediated through genetic variants of the AR. Additionally, our observations confirm that serum testosterone levels have no major implication for spermatogenic efficacy. However, previous studies in nonhuman primates demonstrated that serum testosterone levels do not reflect intratesticular hormone concentrations, and modifications of serum levels do not influence spermatogenesis (30).
In previous studies a clustering of men with extended CAG repeat length was observed among men with infertility caused by unexplained severe impairment of sperm count (7, 25, 31). Results from our cohort confirm the absence of association, as reported in a number of other studies (8, 9, 10). Interpretation of results in men with infertility is confounded by several factors. Idiopathic male infertility, the clinical entity used as an inclusion criterion in all studies, is likely to encompass a set of different underlying genetic and environmental causes that cannot be discriminated by presently available diagnostic tools. Therefore, the composition of such groups, especially with small numbers, strongly influences study outcome.
For reasons unknown to date, expansion of triplet sequences is a dynamic process increasing over generations (32) and predominantly enhanced in the male gender (33). It had already been postulated that children conceived by assisted reproduction may be at an increased risk to develop neurodegenerative diseases characterized by a polyglutamine tract longer than 40 repeats (34). Following this line we postulated that in patients with a familial trait of infertility, extended polyglutamine stretches should be more frequent than in nonfamilial cases. However, we did not detect any differences in the distribution of CAG repeats in these men. The same reservations must be considered for familial cases of infertility. Even if the pattern that we used to identify patients is compatible with an X chromosomal form of inheritance, neurodegenerative diseases linked to CAG repeat length (35) were not reported in any of the families. Hiort et al. (18) recently suggested that AR mutations, indicated by an ASI above 200, are more frequent among men with severely impaired sperm parameters. Although we did not exclude mutations of the AR in our study, the comparable frequency of an elevated ASI among controls (n = 3) and idiopathically infertile men (n = 3) decreases the likelihood of relevant mutations in our population.
To date little effort has been made to understand the remarkable variability of human sperm output between subjects. For mice genetic factors regulating testicular size through number of Sertoli cells have been described (36). In men twin studies suggested a strong familial effect on levels of sex steroids and gonadotropins (37) as well as a familial component in the intersubject variation of sperm concentrations (38). For the first time to our knowledge the present study gives evidence that a polymorphic genetic marker significantly influences the variability of sperm numbers in normal men. The observed effect that CAG repeat numbers are inversely correlated to sperm concentrations indicates that the variable polyglutamine tract size, as determined by CAG repeat numbers in the AR, mediates androgen action with varying intensity, and this different androgenicity of the AR is not reflected by serum testosterone levels themselves.
Acknowledgments
We thank N. Terwort for excellent technical assistance, and Susan Nieschlag, M.A., for language editing of the manuscript.
Footnotes
1 This work was supported by the DFG Confocal Research Group
"The Male Gamete: Production, Maturation, Function" (Ni
130/15). 
Received December 1, 2000.
Revised February 26, 2001.
Accepted March 12, 2001.
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