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The use of clomiphene citrate in the treatment of azoospermia secondary to incomplete androgen resistance
FERTILITY AND STERILITY
Vol. 59, No, 1, January 1993
Copyright 10 1993 The American Fertility Society
Printed on acid-free paper in U.S.A.
The use of clomiphene citrate in the treatment of azoospermia secondary to incomplete androgen resistance
James W, Akin, M.D.* Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana
The phenotype of patients with androgen insensitivity syndrome may range from a 46,XY sex reversed female to a 46,XY infertile male (1). The underlying problem in these patients is thought to be an abnormal androgen receptor (AR) resulting from either aberrations in one of the eight exons contained within the AR gene or from post-translational errors, all in the presence of normal androgen production. As the severity of the androgen receptor abnormality increases, so does the likelihood for development of a female phenotype. Recently, Akin et al. (2) described an azoospermic phenotypic male found to be missing exon four within the AR gene. The AR in this individual must have had some function because the phenotype was male; however, that function must not have been complete enough to allow normal spermatogenesis to occur. Although correction of the abnormal AR is not possible, an increase in the substrate reaching that receptor may result in a more normal biological effect as demonstrated by the following case report. CASE REPORT
A 23-year-old black male presented with azoospermia diagnosed by semen analysis on three separate occasions (average pH of 7.4; average volume of 3.4 mL) over the course of 1 year. Laboratory evaluation revealed a normal follicle-stimulating hormone, luteinizing hormone, testosterone (T), prolactin, and thyroid functions. A peripherallymphocyte karyotype was 46,XY. Physical examination Received June 12, 1992; revised and accepted September 21, 1992. * Reprint requests: James W. Akin, M.D., Department of Obstetrics and Gynecology, Indiana University Hospital, Room 2440, 926 West Michigan Street, Indianapolis, Indiana 46202-5274. Vol. 59, No.1, January 1993
revealed a small left varicocele but otherwise a normal exam. The patient underwent a bilateral testicular biopsy, high ligation of the gonadal vein, and a right-sided vasostomy with vasogram that was normal. On testicular biopsy, most of the tubules contained only Sertoli cells and a slightly thickened tunica propria. Only occasional tubules had germ cells present with varying stages of spermatogenesis. Leydig cells were seen in slightly increased numbers (Fig. 1). Follow-up semen analysis postoperatively still revealed the presence of azoospermia up to 3 years later. The patient and his wife were offered donor insemination for a pregnancy attempt but they declined. Subsequent deoxyribonucleic acid (DNA) study of this patient was accomplished by Southern analysis using oligonucleotide probes specific for the human AR gene. The polymerase chain reaction was also used to confirm the findings. A deletion of exon 4 within the AR gene was found, as has been described elsewhere (2). Treatment with clomiphene citrate (CC) was started at doses of 25 mg/d for 4 months. A subsequent semen analysis revealed 50,000 sperm/mL with 33% motility (total volume was 2.1 mL). The treatment was continued for up to 9 months, but the sperm count did not improve further. No pregnancy was achieved. It was felt that not enough motile sperm were present to perform routine in vitro fertilization (IVF). Potentially, this patient may be a candidate for micromanipulation techniques in the future. DISCUSSION
Aiman et al. (1) published a report in 1979 that first suggested that phenotypically normal infertile Akin
Communications-in-brief
223
1 Figure 1 Testicular biopsy demonstrating predominance of Sertoli cells.
males were a part of the androgen insensitivity spectrum. His conclusions were based on AR binding activity analysis from genital fibroblasts. More recently at the DNA level, Akin et al. (2) demonstrated a molecular deletion of exon 4 within the AR gene in an azoospermic individual with a normal male phenotype. Exon 4 of the AR gene encodes for a protein subunit that facilitates the transport of the AR-androgen complex from the cytoplasm to the nucleus in the target cell. In the absence of exon 4, this process continues but not as efficiently. Phenotypically normal males with azoospermia secondary to androgen resistance may represent a subpopulation of infertile males who might respond to medical therapy. If the AR is present but its complete function is only slightly impaired, the flooding of the receptor with increased levels of endogenous androgen substrate may be sufficient to overcome some problems with spermatogenesis. Although a serum T level in this patient was not obtained during treatment, Sokol et al. (3) have previously demonstrated that the T level rises with CC particularly if Leydig cells are present. Gooren (4) described a 32-year-old black male with oligospermia who had undergone surgical correction for hypospadius, unilateral cryptorchidism, and gynecomastia. Studies on fibroblasts from this patient revealed a decreased AR receptor function. The patient was treated with tamoxifen (10 mg 2 times a day), and his wife conceived after about 20 weeks of therapy. This treatment was repeated two additional times over a 5-year period with successful conception each time.
224
Akin
Communications-in-brief
Perhaps the patient reported by Gooren (4) did not have as severe androgen resistance as did the patient in the present case report because oligospermia and not azoospermia was present. Motile sperm were still found in this patient after 4 months of CC therapy, although the ultimate goal of pregnancy was not reached. This case report is not meant to imply that all patients with oligospermia or azoospermia would benefit from CC therapy or even that empiric treatment should be tried. The patients having androgen resistance as the etiology of their infertility are the most appropriate ones on which to try this therapy. The frequency of androgen resistance among azoospermic and oligospermic patients is not known, but a preliminary report based on genital skin fibroblast receptor analysis suggests it is as high as 40% (5). As more infertile males are screened for androgen resistance, the true incidence may become more evident. SUMMARY
An infertile male with a deletion within the AR gene is discussed. The patient presented with azoospermia and, after daily CC treatment, was found to have sperm within his ejaculate. However, the ultimate goal of pregnancy was not achieved, nor were there enough sperm present to warrant an IVF attempt. Key Words: Azoospermia, male infertility, androgen insensitivity syndrome. REFERENCES 1. Aiman J, Griffin JE, Gazak JM, Wilson JD, MacDonald PC.
2.
3.
4.
5.
Androgen insensitivity as a cause of infertility in otherwise normal men. N Engl J Med 1979;300:223-7. Akin JW, Behzadian A, Tho SPT, McDonough PG. Evidence for a partial deletion in the androgen receptor gene in a phenotypic male with azoospermia. Am J Obstet Gynecol 1991;165:1891-4. Sokol RZ, Steiner BS, Bustillo M, Petersen G, Sweidloff RS. A controlled comparison of the efficacy of clomiphene citrate in male infertility. Fertil Steril 1988;49:865-70. Gooren L. Improvement of spermatogenesis after treatment with the antiestrogen tamoxifen in a man with the incomplete androgen insensitivity syndrome. J Clin Endocrinol Metab 1989;68:1207-10. Aiman J, Griffen JE. The frequency of androgen receptor deficiency in infertile men. J Clin Endocrinol Metab 1982;54: 725-32.
Fertility and Sterility
Vol. 59, No, 1, January 1993
Copyright 10 1993 The American Fertility Society
Printed on acid-free paper in U.S.A.
The use of clomiphene citrate in the treatment of azoospermia secondary to incomplete androgen resistance
James W, Akin, M.D.* Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana
The phenotype of patients with androgen insensitivity syndrome may range from a 46,XY sex reversed female to a 46,XY infertile male (1). The underlying problem in these patients is thought to be an abnormal androgen receptor (AR) resulting from either aberrations in one of the eight exons contained within the AR gene or from post-translational errors, all in the presence of normal androgen production. As the severity of the androgen receptor abnormality increases, so does the likelihood for development of a female phenotype. Recently, Akin et al. (2) described an azoospermic phenotypic male found to be missing exon four within the AR gene. The AR in this individual must have had some function because the phenotype was male; however, that function must not have been complete enough to allow normal spermatogenesis to occur. Although correction of the abnormal AR is not possible, an increase in the substrate reaching that receptor may result in a more normal biological effect as demonstrated by the following case report. CASE REPORT
A 23-year-old black male presented with azoospermia diagnosed by semen analysis on three separate occasions (average pH of 7.4; average volume of 3.4 mL) over the course of 1 year. Laboratory evaluation revealed a normal follicle-stimulating hormone, luteinizing hormone, testosterone (T), prolactin, and thyroid functions. A peripherallymphocyte karyotype was 46,XY. Physical examination Received June 12, 1992; revised and accepted September 21, 1992. * Reprint requests: James W. Akin, M.D., Department of Obstetrics and Gynecology, Indiana University Hospital, Room 2440, 926 West Michigan Street, Indianapolis, Indiana 46202-5274. Vol. 59, No.1, January 1993
revealed a small left varicocele but otherwise a normal exam. The patient underwent a bilateral testicular biopsy, high ligation of the gonadal vein, and a right-sided vasostomy with vasogram that was normal. On testicular biopsy, most of the tubules contained only Sertoli cells and a slightly thickened tunica propria. Only occasional tubules had germ cells present with varying stages of spermatogenesis. Leydig cells were seen in slightly increased numbers (Fig. 1). Follow-up semen analysis postoperatively still revealed the presence of azoospermia up to 3 years later. The patient and his wife were offered donor insemination for a pregnancy attempt but they declined. Subsequent deoxyribonucleic acid (DNA) study of this patient was accomplished by Southern analysis using oligonucleotide probes specific for the human AR gene. The polymerase chain reaction was also used to confirm the findings. A deletion of exon 4 within the AR gene was found, as has been described elsewhere (2). Treatment with clomiphene citrate (CC) was started at doses of 25 mg/d for 4 months. A subsequent semen analysis revealed 50,000 sperm/mL with 33% motility (total volume was 2.1 mL). The treatment was continued for up to 9 months, but the sperm count did not improve further. No pregnancy was achieved. It was felt that not enough motile sperm were present to perform routine in vitro fertilization (IVF). Potentially, this patient may be a candidate for micromanipulation techniques in the future. DISCUSSION
Aiman et al. (1) published a report in 1979 that first suggested that phenotypically normal infertile Akin
Communications-in-brief
223
1 Figure 1 Testicular biopsy demonstrating predominance of Sertoli cells.
males were a part of the androgen insensitivity spectrum. His conclusions were based on AR binding activity analysis from genital fibroblasts. More recently at the DNA level, Akin et al. (2) demonstrated a molecular deletion of exon 4 within the AR gene in an azoospermic individual with a normal male phenotype. Exon 4 of the AR gene encodes for a protein subunit that facilitates the transport of the AR-androgen complex from the cytoplasm to the nucleus in the target cell. In the absence of exon 4, this process continues but not as efficiently. Phenotypically normal males with azoospermia secondary to androgen resistance may represent a subpopulation of infertile males who might respond to medical therapy. If the AR is present but its complete function is only slightly impaired, the flooding of the receptor with increased levels of endogenous androgen substrate may be sufficient to overcome some problems with spermatogenesis. Although a serum T level in this patient was not obtained during treatment, Sokol et al. (3) have previously demonstrated that the T level rises with CC particularly if Leydig cells are present. Gooren (4) described a 32-year-old black male with oligospermia who had undergone surgical correction for hypospadius, unilateral cryptorchidism, and gynecomastia. Studies on fibroblasts from this patient revealed a decreased AR receptor function. The patient was treated with tamoxifen (10 mg 2 times a day), and his wife conceived after about 20 weeks of therapy. This treatment was repeated two additional times over a 5-year period with successful conception each time.
224
Akin
Communications-in-brief
Perhaps the patient reported by Gooren (4) did not have as severe androgen resistance as did the patient in the present case report because oligospermia and not azoospermia was present. Motile sperm were still found in this patient after 4 months of CC therapy, although the ultimate goal of pregnancy was not reached. This case report is not meant to imply that all patients with oligospermia or azoospermia would benefit from CC therapy or even that empiric treatment should be tried. The patients having androgen resistance as the etiology of their infertility are the most appropriate ones on which to try this therapy. The frequency of androgen resistance among azoospermic and oligospermic patients is not known, but a preliminary report based on genital skin fibroblast receptor analysis suggests it is as high as 40% (5). As more infertile males are screened for androgen resistance, the true incidence may become more evident. SUMMARY
An infertile male with a deletion within the AR gene is discussed. The patient presented with azoospermia and, after daily CC treatment, was found to have sperm within his ejaculate. However, the ultimate goal of pregnancy was not achieved, nor were there enough sperm present to warrant an IVF attempt. Key Words: Azoospermia, male infertility, androgen insensitivity syndrome. REFERENCES 1. Aiman J, Griffin JE, Gazak JM, Wilson JD, MacDonald PC.
2.
3.
4.
5.
Androgen insensitivity as a cause of infertility in otherwise normal men. N Engl J Med 1979;300:223-7. Akin JW, Behzadian A, Tho SPT, McDonough PG. Evidence for a partial deletion in the androgen receptor gene in a phenotypic male with azoospermia. Am J Obstet Gynecol 1991;165:1891-4. Sokol RZ, Steiner BS, Bustillo M, Petersen G, Sweidloff RS. A controlled comparison of the efficacy of clomiphene citrate in male infertility. Fertil Steril 1988;49:865-70. Gooren L. Improvement of spermatogenesis after treatment with the antiestrogen tamoxifen in a man with the incomplete androgen insensitivity syndrome. J Clin Endocrinol Metab 1989;68:1207-10. Aiman J, Griffen JE. The frequency of androgen receptor deficiency in infertile men. J Clin Endocrinol Metab 1982;54: 725-32.
Fertility and Sterility