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Original Studies |
Departments of Pediatrics, Medical University of Lübeck (O.H., P.-M.H., B.K., K.K.), City Hospital Wolfsburg (G.H.G.S.), Children’s Hospital Hamburg-Altona (T.H.); Department of Andrology (W.S.), University Hospital Hamburg-Eppendorf; and Department of Obstetrics and Gynecology (M.B.P.), Medical University of Lübeck, Germany
Address correspondence and requests for reprints to: Olaf Hiort, M.D., Department of Pediatrics, Medical University of Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. E-mail: hiort{at}paedia.ukl.mu-luebeck.de
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Abstract |
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We studied 180 males with variable impairment of spermatogenesis. In all patients, serum levels of testosterone and gonadotropins were analyzed to define an androgen sensitivity index (ASI). Single-strand conformation analysis and direct DNA sequencing of PCR-amplified blood leukocyte DNA were used to identify mutations within the whole coding region of the AR-gene. Endocrine and molecular investigations were compared with 53 normal males with proven fertility.
In three infertile males, mutations in the AR were identified. Two unrelated males had the same variation within the first exon encoding for the transactivation domain of the receptor (Pro390Ser), whereas, in the third, a mutation in the hormone-binding region was characterized (Gln798Glu). All identified mutation carriers had a significantly elevated ASI.
A proportion of males with idiopathic infertility carry relevant variations within the AR-gene. These males may be distinguished on the basis of hormone levels, calculating the ASI, although this index lacks specificity.
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Introduction |
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Germline mutations in the AR-gene usually lead to a defect of virilization in karyotypic males despite normal, or even supraphysiologic, androgen levels. The phenotype of affected individuals varies considerably, depending on the type and localization of these mutations. It ranges from unequivocally female, without any androgenic effects over partial androgen insensitivity characterized by genital ambiguity, to males with undervirilization (2). Because of an impaired AR-mediated regulatory mechanism of the gonadotropin-androgen axis, both LH and testosterone (T) in serum may be elevated, leading to a distinctively high value of the LH x T multiplication product. This value has previously been termed as the androgen sensitivity index (ASI) (3). The majority of alterations within the AR-gene are point mutations with subsequent amino acid substitutions, destructing AR-function and diminishing androgen response. However, selective mechanisms of androgen action, i.e. specific support of external virilization or spermatogenesis, have not been demonstrated yet to be altered conversely by such mutations in vivo. This may be different for changes in the size of one of the two trinucleotide repeat polymorphisms within the transactivation domain of the receptor. Expansion of the polyglutamine tract above the normal range is associated with adult onset of spinal and bulbar muscular atrophy (Kennedy’s disease). Affected males also demonstrate signs of androgen insensitivity and infertility. Two reports recently proposed that longer polyglutamine tracts within the normal range increased the risk of impaired spermatogenesis in otherwise normal males (4, 5). These data would indicate a direct relation between the length of this AR-specific variable polymorphic region and defective sperm maturation caused by decreased functional competence of the AR. However, these findings have been challenged both by us and others (6, 7), indicating that a correlation between the variable CAG (polyglutamine)-repeat length in the AR-gene and male infertility cannot be made in Caucasians.
Moreover, the importance of infertility in males, caused by defects in the AR, has been discussed quite controversially on the ground of biochemical analysis of specific androgen binding in genital skin fibroblasts. These older studies proposed, as a cause for male infertility, that between 0% (irrelevance of androgen insensitivity) and 40% of all infertile males are affected by defective androgen binding (3, 8, 9, 10, 11, 12). With the knowledge of the genetic structure of the AR-gene, molecular analysis based on PCR methodology has been reported for males with idiopathic infertility in newer research papers; however, most of these publications were either single-case reports or covered only part of the AR-gene (13, 14, 15, 16, 17, 18, 19, 20, 21). The aim of our present study was to investigate a large cohort of males with infertility and impaired spermatogenesis of unknown cause, for variations within the coding region of the AR-gene. Results were correlated with biochemical endocrinological findings and spermatologic values and compared with a normal control group.
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Subjects and Methods |
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One hundred eighty patients, 20.9–54.4 yr old, were referred, between 1993 and 1997, from the Department of Andrology at the University Hospital Hamburg-Eppendorf and the Department of Obstetrics and Gynecology at the Medical University of Lübeck (both regional centers of andrology) for molecular analysis. All patients had had a period of at least 2 yr of unfulfilled fertility. Clinical investigations by experienced andrologists covered the exclusion of known causes of male infertility as overt virilization disorders (e.g. hypospadias, gynecomastia) and other genetic (e.g. chromosomal aberrations, such as Klinefelter syndrome and genetic abnormalities as cystic fibrosis, endocrine (e.g. hypogonadotropic hypogonadism and prolactinoma), infectious, or obstructive causes (e.g. congenital bilateral aplasia of the vasa deferentia). Clinical work-up also covered questions regarding libido and shaving frequency, as well as a family history.
Routinely, hormonal status was requested and included values for LH, FSH, and T by commercially available RIAs. Ejaculates were investigated at least 2 times on different occasions, according the guide lines of the World Health Organization (22). One hundred ten patients showed oligoteratozoospermia (<10 million sperm/mL ejaculate, <30% normal forms), 57 had teratozoospermia (<30% normal sperm), and 13 patients suffered from azoospermia. Informed consent was obtained from all patients for experimental molecular investigations, and EDTA-blood was drawn at routine venopuncture.
Fifty-three Caucasian males served as controls. Fertility was assured, because all had fathered at least one child. Spermiograms were not available in these cases. These males consented to a single blood draw for serum analysis of LH, FSH, and T , as well as molecular genetic studies from blood leukocyte DNA.
DNA analysis
The whole coding region of the AR gene, including intron/exon junctions, was amplified from blood leukocyte-derived DNA, by PCR, in 14 segments as described previously (23). While exons 2–8 were separately amplified and each amplification product spanned completely a single exon, primers were designed to amplify the first exon in 7 overlapping segments. All PCR-products were subjected to nonisotopic single-strand conformation analysis for the detection of point mutations as described previously (23). In addition to the negative control DNA samples of males with proven fertility, 65 positive control samples with previously detected point mutations within one of the exons or segments were included in the study. Sequencing of variations was performed on an automated sequencer (ALF Express II, Amersham Pharmacia Biotech, Freiburg, Germany) employing cycle sequencing protocols provided by the manufacturer. To assess the length of the variable CAG (polyglutamine) and GGN (polyglycine) trinucleotide polymorphisms within the first exon of the AR, additional PCR products were electrophoresed on nondenaturing polyacrylamide gels with adequate size markers and visualized with silver staining. Additionally, selected samples were sequenced to determine the exact number of CAG or GGN-repeats, and these control samples were included in each electrophoresis. Determination of the repeat-sizes was performed on a computerized analysis system (ImageMaster, Amersham Pharmacia Biotech).
Assessment of mutant AR function in vitro
The two mutations Pro390Ser and Gln798Glu were introduced into the AR expression vector pSVAR0 (a kind gift of Dr. A. O. Brinkmann, Erasmus University, Rotterdam, The Netherlands), employing the QuikChange Site-Directed Mutagenesis kit (Stratagene, La Jolla, CA) according to the instructions supplied by the manufacturer and as described previously (24).
Cultured Chinese hamster ovary cells were maintained at 37 C in 5%
CO2 with DMEM F12 (Life Technologies, Karlsruhe, Germany), 5% FCS, and
antibiotics. Transfections were performed using the
Ca2+ phosphate precipitation method. Then, 50
ng/mL of either wild-type or mutant AR expression plasmid was
transfected. In addition, 2 µg/mL of mouse mammary tumor virus
(MMTV)-luciferase reporter plasmid (Organon, Oss, The
Netherlands), 10 ng/mL of constitutively expressed pRL-SV40
Renilla luciferase plasmid (Promega Corp., Madison, WI),
and 17.9 µg pTZ19 carrier plasmid were cotransfected. Firefly
luciferase counts were corrected for transfection efficiency by Renilla
luciferase activity, both determined using the Dual Luciferase Reporter
gene assay (Promega Corp.). For investigation of
transactivation activity, cells were incubated with increasing
concentrations of either dihydrotestosterone or T (see Fig. 3
). Each
transfection was done in triplicate, and three independent experiments
were performed. The two mutant plasmids and the wild-type AR plasmid
were always assayed in parallel, for means of comparability of
results.
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Results |
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Hormonal values within the group of infertile males were as follows. The mean for FSH was 8.4 U/L (range, 1.3–94.0); for LH, 3.5 U/L (range, 0.4–29.0); and for T, 20.5 nmol/L (range, 6.2–69.3). Absolute values for serum T and LH were multiplied with each other to determine the ASI. The mean for this index was 58.9 U x nmol/L2 (range, 6.2–499.2). Within the control group, the mean for LH was 3.7 U/L (range, <0.1–8.5); for FSH, 4.8 U/L (range, 1.0–14.5); and for T, 14.7 nmol/L (range, 5.9–34.7). The mean for the ASI was found to be 54.1 U x nmol/L2 (range, 6.7–138.7). In comparison with the normal control group, 39 of the 180 infertile males had an ASI above the normal range.
Molecular genetic analysis of the AR-gene
PCR-amplification was successfully achieved for the whole coding region in all patients and controls investigated, and no gross abnormalities were detected in any of the patients’ DNA samples. Employing single-strand conformation analysis, several variations were encountered and subjected to sequencing. Within the second fragment of exon 1, a similar abnormality was found in 33 of 180 patients (18.3%), as well as in 11 of 53 normal fertile males (20.8%). Sequencing revealed a nucleotide substitution in codon position 211 (GAG-GAA), which does not alter the encoded amino acid glutamate (data not shown). This variation has been well described by us and others as a naturally occurring polymorphism (25).
In three patients, nucleotide substitutions were characterized that
alter the predicted amino acid sequence of the AR (Table 1). In two unrelated patients (B 386 and
B 236), a cytidine-to-thymidine substitution in exon 1 leads to an
exchange of the normally present proline by serine
(CCG-TCG) (Fig. 1).
Both patients with this abnormality had a decreased sperm count with a
high percentage of abnormal sperm (Table 1). A third patient (B 388)
exhibited an abnormality in exon 6, where a cytidine-to-guanine
substitution leads to a predicted glutamine-to-glutamic acid exchange
in codon position 798 (CAA-GAA) (Fig. 1). In all three patients, the
ASI was highly elevated above the range of the normal control group
(normal < 138 U x nmol/L2).
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We had determined both the length of the CAG- and the GGN-repeats
within the first exon of the AR-gene in both the patient and the
control group. Investigation of the CAG-repeat had revealed a mean of
23 repeats (range, 13–30) in the patient group; whereas in the control
group, the mean was 24 repeats (range, 17–39) (see Ref. 6). Also for
the GGN-repeat, no significant difference was found between the patient
and control groups. For all infertile males, the mean was 22
GGN-repeats (range, 13–27); in the control group, the mean was 23
repeats (range, 17–27) (Fig. 2). The
Wilcoxon/Mann-Whitney test was used for statistical analysis and
revealed no statistical difference between either group for both the
length of the CAG and GGN-repeat.
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The mutated Glu798AR displayed a
differential pattern of partial transcriptional deficiency in the
luciferase assay. Incubation of the cells with dihydrotestosterone
showed only minimal receptor impairment, compared with the wild-type
AR. However, in the presence of T , reporter gene induction was reduced
and could not be overcome by increasing ligand concentrations (Fig. 3
). In contrast to the
Glu798AR, the Ser390AR did
not lead to gross alterations of transcriptional activity, compared
with the wild-type AR in the presence of both hormones (Fig. 3). AR
protein expression levels, as assessed by Western immunoblotting of
transfected Chinese hamster ovary cells, displayed no apparent
differences among the three constructs (data not shown).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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An elevated ASI has been suggested previously as an indication of androgen insensitivity, because the elevation of both LH and T was interpreted as an impaired negative feedback control of the hypothalamic-pituitary-testicular axis (3). In all 3 patients with mutations of the AR-gene in our study, the ASI was between 230.9 and 405.6 U x nmol/L2, thus, strikingly higher than in the control group (normal range in the control cohort, <138 U x nmol/L2). We believe that the determination of the ASI can be useful in identifying patients at risk for a minimal form of androgen insensitivity caused by mutation of the AR. Our results may be interpreted to mean that patients who do not display an elevated ASI are not likely to carry mutations in the AR gene. In contrast, 39 infertile males of our cohort had an ASI above the determined normal range in the control group. Thus, only a minority of infertile males with an elevated ASI above the normal range had mutations in the AR-gene. Most likely this is because of the low specificity of this endocrine abnormality, as, for instance, in estrogen insufficiency, LH and T are also elevated as a sign of a defective feedback control on gonadotropins (26). However, only 9 patients had an ASI more than 200 U x nmol/L2. Thus, we propose that the higher the ASI, the more likely an abnormality within the AR-gene.
All three mutation carriers had oligoteratozoospermia with severely
deformed sperm (Table 1). Recently, Tesarik et al. (27)
demonstrated that T potentiates the effects of FSH because of
prevention of Sertoli cell apoptosis. It is also known, that FSH
regulates AR expression in Sertoli cells (28). These experiments
support our clinical findings that variations of the AR may interfere
with mechanisms of sperm maturation rather than cause complete absence
of spermatogenesis.
Two different mutational mechanisms within the AR gene are of interest in infertile males: variable polymorphisms, and mutations in the conserved regions. In contrast to previous studies (3, 4), we found no abnormalities within either trinucleotide repeat polymorphism of the AR, in comparison to the control group, nor did Giwercman and co-workers in their recent study on a Swedish population (5, 6). Thus, the role of polyglutamine repeat expansion within the AR gene in infertile males remains questionable. Moreover, in our study, no presymptomatic patients with Kennedy’s disease were detected. Also, investigations of the polyglycine repeat revealed no deviation from the normal control group. Thus, elongation or reduction of this variable repeat region within the AR does not play a significant role in male infertility.
Point mutations leading to amino acid substitutions represent the most
important mechanism of AR abnormalities in all patients with androgen
insensitivity syndrome. Though two unrelated patients with similar ASI
and impairment of spermatogenesis carry a previously unreported point
mutation within the first exon altering the amino acid structure of the
transactivation domain (Pro390Ser), the mutation Gln798Glu within the
hormone binding region has been described by us and others previously
(1, 15, 28). Cotransfections of the mutant AR construct
Glu798 displayed a partial loss of
androgen-induced transcriptional activity. However, the phenotype of
patients with this mutation is highly variable. Bevan et al.
and we ourselves (1, 29) have described patients carrying the Glu798Gln
mutation who presented with a severe virilization defect characterized
by predominantly female external genitalia. The occurrence of
completely normal external virilization with only severely impaired
spermatogenesis caused by this mutation is much less clear with respect
to the transactivation deficit demonstrated in vitro (Fig. 3b). Thus, the in vitro studies can hardly reflect the
changes induced in vivo, because the in vitro
model is highly oversimplified to explain the differential pattern
leading to defective spermatogenesis. The differential response to
dihydrotestosterone, compared with T, suggests that the Gln798Glu
mutation may cause a more subtle defect, particularly impairing
spermatogenesis attributable to selective response to different
androgens.
Correlation of in vitro function of the Ser390 AR with the phenotype of impaired spermatogenesis in the two affected subjects is also limited. Interestingly, this mutation is located within a region of the AR that is important for transcriptional activity (30). Moreover, a Pro390Asp mutation of the AR gene has been reported in association with complete AIS, marking the importance of this amino acid residue (31). The endocrine abnormalities of the two patients with this mutation, both characterized by the elevated ASI, suggest a functional defect of the Ser390AR in vivo. We may assume that interactions of currently unknown cofactors of the AR that are important for normal receptor function in vivo could be affected by the Pro390Ser mutation characterized in our cohort; however, this remains to be proven.
Thus, the in vivo mechanism leading to such highly variable phenotypes of the described mutations, and their molecular impact on spermatogenesis, still have to be further elucidated. However, the assessment of mutations of the AR gene is of severe importance in clinical medicine: The transmission of an AR defect in reproductive procedures may lead to a more severely affected offspring in future generations. Therefore, infertile males carrying genetic variations have to be identified and counseled accordingly before in vitro fertilization procedures (5).
We conclude that AR gene mutations may play an important role as genetic determinants of male infertility. In contrast to other genetic markers of male infertility, patients with AR-gene mutations can be preselected on the basis of endocrine evaluation. Molecular analysis of the AR gene should be instituted in males with a highly abnormal ASI. Whether infertile men with AR gene mutations generally respond favorably to conservative treatment options remains to be investigated. Future identification of molecular abnormalities of the AR gene in normally virilized males with impairment of spermatogenesis will give exciting new insights into different receptor mechanisms and alternatively mediated androgen action and their relevance in human disease.
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Acknowledgments |
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Footnotes |
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Received December 30, 1999.
Revised April 12, 2000.
Accepted April 25, 2000.
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References |
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