- Email: [email protected]
Male Infertility
MALE INFERTILITY
Methods. We retrospectively reviewed the medical records of 24 patients who underwent an experimental intravesical treatment with BCG plus interferon alpha-2b or valrubicin for transitional cell carcinoma of the bladder. All patients had Stage Tis and/or T1 transitional cell carcinoma and had failed multiple prior courses of intravesical therapy, including at least one course of BCG. Results. Patients were followed up for a median of 28.5 months (range 6 to 48). One patient died of unrelated disease. All other patients were alive at last follow-up. Fourteen patients with preserved bladder were continuing cystoscopic surveillance: four had no recurrence, five had recurrence limited to the mucosa (Ta or Tis) and became free of disease after an additional course of intravesical therapy, and five had recurrent Ta or Tis or positive cytologic findings. The remaining 9 patients underwent radical cystectomy. All pathologic specimens showed no evidence of progression to muscle-invasive disease. Tis of the resected ureters in 6 and involvement of the prostate in 4 of the 9 patients (three in the urethral ducts and glands and one in the prostatic stroma) were noted. Conclusions. A select group of patients with BCG-refractory transitional cell carcinoma and a poor surgical risk for cystectomy may benefit from continued intravesical therapy without a significant risk of progression. However, a cautious approach to this treatment modality is recommended, and very close follow-up is necessary to detect bladder recurrences and involvement of the upper tract and prostatic urethra. Editorial Comment: The authors describe a group of patients with high risk superficial urothelial cancers apparently refractory to 1 trial of intravesical BCG. When these patients were followed with additional intravesical BCG, interferon, or BCG plus interferon or valrubicin, they did not appear to have progressive disease at a median interval of 28.5 months (range 6 to 48). This study presents a number of issues that make its interpretation less clear than is suggested by the authors. First, the patients are described as poor surgical risk for cystectomy. However, 9 of the patients underwent radical cystectomy. While none of these cases showed evidence of progression to muscle invasive disease, carcinoma in situ was detected in the distal ureter in 6 and in the prostate in 4 (urethral ducts/glands in 3 and stroma in 1). Such findings are indicative of the manner in which these cases fail with progressive disease, and it would probably have been only a matter of time until they manifested progression and likely metastatic disease. Median duration of disease history prior to patient referral was 56 months, and 13 of 24 patients had previously received intravesical BCG treatment, of whom 11 received intravesical BCG plus chemotherapy. Here the issue is the interval required for “high risk” disease to become progressive, and the window during which such cases can be cured by excision of nonresponsive disease. Of the 14 patients who were followed cystoscopically 4 had an apparent complete response to BCG plus interferon, but the definition of this response and its durability is unclear. At least half of the patients with high risk disease who do not demonstrate a prompt response to these treatments likely will fail with progressive disease, while others, if followed long enough, will also have a strong possibility of failing. The implied uncertainty of the time course of disease in relation to the ability of patients to undergo cystectomy versus an estimate of their life expectancy should be considered strongly in determining whether it is safe to forestall definitive treatment. Michael J. Droller, M.D.
MALE INFERTILITY Effect of Paternal Age on Human Sperm Chromosomes E. M. P. SARTORELLI, L. F. MAZZUCATTO AND J. M. DE PINA-NETO, University of Sa˜ o Paulo, Ribeira˜ o Preto, Sa˜ o Paulo, Brazil Fertil Steril, 76: 1119 –1123, 2001 Objective: To investigate whether increased age alters the frequency and type of chromosomal anomalies in human spermatozoa. Design: Semen specimens were collected from donors via masturbation; cytogenetic studies were performed on sperm chromosomes after heterologous (human-hamster) in vitro fertilization. Setting: Cytogenetics Laboratory, Genetics Department, Faculty of Medicine of Ribeira˜ o Preto, University of Sa˜ o Paulo, Brazil. Patients(s): Seven men ages 59 –74 (older group) and five men ages 23–39 (control group). Main Outcome Measure(s): Frequency and types of chromosomal anomalies in older and control group donors. Result(s): The frequency of numerical and structural aberrations (acentric fragments and complex radial
859
860
MALE INFERTILITY
figures) was significantly greater in chromosomes of older donors when compared with those of the control group. Conclusion(s): The higher frequency of sperm chromosome aberrations in older men was mainly a result of increased nondisjunction, acentric fragments, and complex radial figures. Editorial Comment: This study showed a small but significant increase in the frequency of sperm chromosomal abnormalities in older healthy men. Whether this finding is clinically significant may depend on whether these abnormal sperm end up fertilizing eggs in vivo. Karyotyping sperm is extremely labor-intensive, and although many individual sperm were studied, the number of volunteers in the 2 groups was only 5 and 7. These numbers may not be sufficient to detect significant differences. In spite of this, one can conclude from this study that the risk of chromosomal defects in the offspring of men with advanced age is not large, even if it is higher than that of younger men. Jonathan P. Jarow, M.D. Long Term Outcome in Adult Males With Classic Congenital Adrenal Hyperplasia M. S. CABRERA, M. G. VOGIATZI AND M. I. NEW, Department of Pediatrics, New York Presbyterian HospitalWeill Medical College of Cornell University, New York, New York J Clin Endocrinol Metab, 86: 3070 –3078, 2001 The effects of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency on final height and fertility were evaluated in 30 affected males, aged 17– 43 yr. The mean adult height of these patients was 165.64 ⫾ 8.4 cm (mean ⫾ SD), with a mean SD score of ⫺1.65 ⫾ 1.2 cm. The difference between the mean final height SD score and mean target height SD score was ⫺1.67 ⫾ 1.0 cm. All patients had short stature and did not reach their estimated target heights. There was no difference in height SD score between the salt-wasting and simple virilizing CAH patients. No correlation between the final height and degree of hormonal control or bone age advancement was observed. Of the 30 subjects, 18 had testicular sonograms. Abnormal sonogram findings of testicular adrenal rests were present in 9 patients (group 1), whereas sonogram without adrenal rests comprised the remaining 9 patients (group 2). In group 1, 8 of 9 patients and in group 2, 4 of 9 patients were salt-wasters; the remainder were simple virilizers. In group 1, 7 of 9 patients had semen analysis, and all were judged infertile. Of the 6 patients in group 2 who had semen analysis, 1 was azoospermic, and the remainder were normal. During optimal adrenal hormone suppression, gonadotropins at baseline and after GnRH stimulation were significantly higher in group 1 than in group 2, reflecting the loss of Leydig cell function to secrete testosterone. In conclusion, adult males affected with CAH due to 21-hydroxylase deficiency do not achieve the height predicted from parental heights. The presence of adrenal rests within the testes of adult males with classic CAH are more frequent in the salt-wasting form and are associated with a higher risk for infertility. Editorial Comment: Congenital adrenal hyperplasia is caused by a genetic abnormality of an enzyme involved in steroidogenesis, the most common one being 21-hydroxylase. The presentation includes ambiguous genitalia in the newborn, metabolic abnormalities such as salt wasting, precocious puberty and, occasionally, infertility as an adult. This study looked at the long-term outcome of a group of men with treated classic congenital adrenal hyperplasia. The treatment was replacement of glucocorticoids and mineralocorticoids, which suppress the inappropriately high adrenocorticotropic hormone secretion and excess production of other steroids by the adrenal glands. It turns out that many men with this disorder are fertile, and that in the experience of the authors the presence of adrenal rests within the testes on ultrasonography is a bad prognostic sign. It is not clear on the basis of this small series whether the adrenal rests within the testes of these men were the cause of their infertility, or a reflection of the severity of their disease or the adequacy of steroid replacement. Jonathan P. Jarow, M.D. Serum Sperm Antibodies Are Not Elevated After Mumps Orchitis S. KALAYDJIEV, D. DIMITROVA, M. NENOVA, S. PENEVA, I. DIKOV AND L. NAKOV, Medical University of Sofia, Sofia and Medical University of Varna, Varna, Bulgaria Fertil Steril, 77: 76 – 82, 2002 Objective: To assess the level of serum sperm antibodies after mumps orchitis. Design: Controlled descriptive study. Setting: Academic research environment. Patient(s): Seventy-four mumps orchitis patients. Intervention(s): Sampling of serum at different intervals after the onset of orchitis symptoms: 1 to 7 days, 31 to 60 days, and 61 to 431 days. Main Outcome Measure(s): Level of serum sperm antibodies, using Kibrick’s gelatin agglutination test, Friberg’s tray agglutination test, Isojima’s sperm immobilization test, and ELISA. Result(s): Clinically relevant sperm antibody values were detected by the Friberg method among patients
Methods. We retrospectively reviewed the medical records of 24 patients who underwent an experimental intravesical treatment with BCG plus interferon alpha-2b or valrubicin for transitional cell carcinoma of the bladder. All patients had Stage Tis and/or T1 transitional cell carcinoma and had failed multiple prior courses of intravesical therapy, including at least one course of BCG. Results. Patients were followed up for a median of 28.5 months (range 6 to 48). One patient died of unrelated disease. All other patients were alive at last follow-up. Fourteen patients with preserved bladder were continuing cystoscopic surveillance: four had no recurrence, five had recurrence limited to the mucosa (Ta or Tis) and became free of disease after an additional course of intravesical therapy, and five had recurrent Ta or Tis or positive cytologic findings. The remaining 9 patients underwent radical cystectomy. All pathologic specimens showed no evidence of progression to muscle-invasive disease. Tis of the resected ureters in 6 and involvement of the prostate in 4 of the 9 patients (three in the urethral ducts and glands and one in the prostatic stroma) were noted. Conclusions. A select group of patients with BCG-refractory transitional cell carcinoma and a poor surgical risk for cystectomy may benefit from continued intravesical therapy without a significant risk of progression. However, a cautious approach to this treatment modality is recommended, and very close follow-up is necessary to detect bladder recurrences and involvement of the upper tract and prostatic urethra. Editorial Comment: The authors describe a group of patients with high risk superficial urothelial cancers apparently refractory to 1 trial of intravesical BCG. When these patients were followed with additional intravesical BCG, interferon, or BCG plus interferon or valrubicin, they did not appear to have progressive disease at a median interval of 28.5 months (range 6 to 48). This study presents a number of issues that make its interpretation less clear than is suggested by the authors. First, the patients are described as poor surgical risk for cystectomy. However, 9 of the patients underwent radical cystectomy. While none of these cases showed evidence of progression to muscle invasive disease, carcinoma in situ was detected in the distal ureter in 6 and in the prostate in 4 (urethral ducts/glands in 3 and stroma in 1). Such findings are indicative of the manner in which these cases fail with progressive disease, and it would probably have been only a matter of time until they manifested progression and likely metastatic disease. Median duration of disease history prior to patient referral was 56 months, and 13 of 24 patients had previously received intravesical BCG treatment, of whom 11 received intravesical BCG plus chemotherapy. Here the issue is the interval required for “high risk” disease to become progressive, and the window during which such cases can be cured by excision of nonresponsive disease. Of the 14 patients who were followed cystoscopically 4 had an apparent complete response to BCG plus interferon, but the definition of this response and its durability is unclear. At least half of the patients with high risk disease who do not demonstrate a prompt response to these treatments likely will fail with progressive disease, while others, if followed long enough, will also have a strong possibility of failing. The implied uncertainty of the time course of disease in relation to the ability of patients to undergo cystectomy versus an estimate of their life expectancy should be considered strongly in determining whether it is safe to forestall definitive treatment. Michael J. Droller, M.D.
MALE INFERTILITY Effect of Paternal Age on Human Sperm Chromosomes E. M. P. SARTORELLI, L. F. MAZZUCATTO AND J. M. DE PINA-NETO, University of Sa˜ o Paulo, Ribeira˜ o Preto, Sa˜ o Paulo, Brazil Fertil Steril, 76: 1119 –1123, 2001 Objective: To investigate whether increased age alters the frequency and type of chromosomal anomalies in human spermatozoa. Design: Semen specimens were collected from donors via masturbation; cytogenetic studies were performed on sperm chromosomes after heterologous (human-hamster) in vitro fertilization. Setting: Cytogenetics Laboratory, Genetics Department, Faculty of Medicine of Ribeira˜ o Preto, University of Sa˜ o Paulo, Brazil. Patients(s): Seven men ages 59 –74 (older group) and five men ages 23–39 (control group). Main Outcome Measure(s): Frequency and types of chromosomal anomalies in older and control group donors. Result(s): The frequency of numerical and structural aberrations (acentric fragments and complex radial
859
860
MALE INFERTILITY
figures) was significantly greater in chromosomes of older donors when compared with those of the control group. Conclusion(s): The higher frequency of sperm chromosome aberrations in older men was mainly a result of increased nondisjunction, acentric fragments, and complex radial figures. Editorial Comment: This study showed a small but significant increase in the frequency of sperm chromosomal abnormalities in older healthy men. Whether this finding is clinically significant may depend on whether these abnormal sperm end up fertilizing eggs in vivo. Karyotyping sperm is extremely labor-intensive, and although many individual sperm were studied, the number of volunteers in the 2 groups was only 5 and 7. These numbers may not be sufficient to detect significant differences. In spite of this, one can conclude from this study that the risk of chromosomal defects in the offspring of men with advanced age is not large, even if it is higher than that of younger men. Jonathan P. Jarow, M.D. Long Term Outcome in Adult Males With Classic Congenital Adrenal Hyperplasia M. S. CABRERA, M. G. VOGIATZI AND M. I. NEW, Department of Pediatrics, New York Presbyterian HospitalWeill Medical College of Cornell University, New York, New York J Clin Endocrinol Metab, 86: 3070 –3078, 2001 The effects of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency on final height and fertility were evaluated in 30 affected males, aged 17– 43 yr. The mean adult height of these patients was 165.64 ⫾ 8.4 cm (mean ⫾ SD), with a mean SD score of ⫺1.65 ⫾ 1.2 cm. The difference between the mean final height SD score and mean target height SD score was ⫺1.67 ⫾ 1.0 cm. All patients had short stature and did not reach their estimated target heights. There was no difference in height SD score between the salt-wasting and simple virilizing CAH patients. No correlation between the final height and degree of hormonal control or bone age advancement was observed. Of the 30 subjects, 18 had testicular sonograms. Abnormal sonogram findings of testicular adrenal rests were present in 9 patients (group 1), whereas sonogram without adrenal rests comprised the remaining 9 patients (group 2). In group 1, 8 of 9 patients and in group 2, 4 of 9 patients were salt-wasters; the remainder were simple virilizers. In group 1, 7 of 9 patients had semen analysis, and all were judged infertile. Of the 6 patients in group 2 who had semen analysis, 1 was azoospermic, and the remainder were normal. During optimal adrenal hormone suppression, gonadotropins at baseline and after GnRH stimulation were significantly higher in group 1 than in group 2, reflecting the loss of Leydig cell function to secrete testosterone. In conclusion, adult males affected with CAH due to 21-hydroxylase deficiency do not achieve the height predicted from parental heights. The presence of adrenal rests within the testes of adult males with classic CAH are more frequent in the salt-wasting form and are associated with a higher risk for infertility. Editorial Comment: Congenital adrenal hyperplasia is caused by a genetic abnormality of an enzyme involved in steroidogenesis, the most common one being 21-hydroxylase. The presentation includes ambiguous genitalia in the newborn, metabolic abnormalities such as salt wasting, precocious puberty and, occasionally, infertility as an adult. This study looked at the long-term outcome of a group of men with treated classic congenital adrenal hyperplasia. The treatment was replacement of glucocorticoids and mineralocorticoids, which suppress the inappropriately high adrenocorticotropic hormone secretion and excess production of other steroids by the adrenal glands. It turns out that many men with this disorder are fertile, and that in the experience of the authors the presence of adrenal rests within the testes on ultrasonography is a bad prognostic sign. It is not clear on the basis of this small series whether the adrenal rests within the testes of these men were the cause of their infertility, or a reflection of the severity of their disease or the adequacy of steroid replacement. Jonathan P. Jarow, M.D. Serum Sperm Antibodies Are Not Elevated After Mumps Orchitis S. KALAYDJIEV, D. DIMITROVA, M. NENOVA, S. PENEVA, I. DIKOV AND L. NAKOV, Medical University of Sofia, Sofia and Medical University of Varna, Varna, Bulgaria Fertil Steril, 77: 76 – 82, 2002 Objective: To assess the level of serum sperm antibodies after mumps orchitis. Design: Controlled descriptive study. Setting: Academic research environment. Patient(s): Seventy-four mumps orchitis patients. Intervention(s): Sampling of serum at different intervals after the onset of orchitis symptoms: 1 to 7 days, 31 to 60 days, and 61 to 431 days. Main Outcome Measure(s): Level of serum sperm antibodies, using Kibrick’s gelatin agglutination test, Friberg’s tray agglutination test, Isojima’s sperm immobilization test, and ELISA. Result(s): Clinically relevant sperm antibody values were detected by the Friberg method among patients