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Re: Impact of Chemotherapeutics and Advanced Testicular Cancer or Hodgkin Lymphoma on Sperm Deoxyribonucleic Acid Integrity
2280
MALE INFERTILITY
in oligozoospermic patients were AZFc deletions. Seven hundred eighteen patients underwent microdissection TESE, including 41 with microdeletions. Microdissection TESE failed in all patients with AZFa, AZFb, AZFb⫹c, and complete Yq deletions. Sperm were retrieved in 15/21 AZFc deleted patients (71.4%). The presence of an AZFc deletion was associated with increased likelihood of sperm retrieval when compared with the 48.8% retrieval rate in 385 idiopathically azoospermic men who consecutively underwent microdissection TESE at our institution during the study period. Clinical pregnancy was achieved in 10/15 azoospermic AZFc deleted patients for whom sperm were successfully retrieved. Conclusion(s): Of azoospermic and severely oligozoospermic American men, 10% harbor Y microdeletions that alter prognosis for surgical sperm retrieval and are vertically transmissible. Y microdeletion testing is essential for genetic and preoperative counseling in these patients. Editorial Comment: The usefulness of Y chromosomal microdeletion testing is twofold. If positive, you can counsel your patient that he will transmit it to male offspring, and if, as these authors observe, it is an AZFa, AZFb, AZFbⴙc or complete Yq deletion, the chance of retrieving sperm by extraction is diminishingly small, probably zero. A problem arises when the test is negative, which it most often is. We are not currently screening for the likely hundreds of genes involved in male reproduction because we do not yet know what they are. Consequently we must counsel all of our patients that the cause of their reproductive issues may be genetic, and that they must consider the possibility of transmission of unknown genetic mutations to offspring with artificial reproductive techniques. The problem with the emphatic statement that “Y microdeletion testing is essential for genetic and preoperative counseling” in patients with azoospermia and severe oligospermia is that patients need to be counseled about possible transmission of genetic mutations regardless of the results. Also, the likelihood of finding an AZFa, AZFb, AZFbⴙc or complete Yq deletion, where preoperative counseling actually matters, is low and varies greatly among geographic regions. Thus, the cost/benefit analysis must be entertained by an individual physician in his or her own practice. A better conclusion would encourage physicians to determine the incidence of AZFa, AZFb, AZFbⴙc or complete Yq deletions in their own practices, and to speak openly with patients about implications of testing based on regionally derived data. Craig Niederberger, M.D.
Re: Impact of Chemotherapeutics and Advanced Testicular Cancer or Hodgkin Lymphoma on Sperm Deoxyribonucleic Acid Integrity C. O’Flaherty, B. F. Hales, P. Chan and B. Robaire Department of Pharmacology and Therapeutics, McGill University Health Centre, Montreal, Quebec, Canada Fertil Steril 2010; 94: 1374 –1379.
Objective: To determine the impact of combination chemotherapy on the quality of newly generated spermatozoa from patients with advanced testicular cancer and patients with Hodgkin lymphoma (HL). Design: Prospective longitudinal study. Setting: Academic facility. Patient(s): Patients with newly diagnosed metastatic testicular cancer and with HL that required chemotherapy were compared with age-matched healthy community volunteers. Intervention(s): None. Main Outcome Measure(s): Semen parameters, hormone levels, testis volume, and presence of sperm DNA strand breaks in patients with cancer and in healthy community volunteers were compared before and after the patients’ chemotherapy at 6, 12, 18, and 24 months. Result(s): Before chemotherapy, both cancer groups had poorer semen quality compared with community volunteers. Among patients with testicular cancer and HL, 67% and 60%, respectively, had ⬍5x10(6) sperm/mL at 6 months after chemotherapy. At 24 months, 60% and 57% of patients with testicular cancer and HL, respectively, had normal sperm concentrations. Level of FSH was significantly higher in the cancer group compared with community volunteers at 6 to 12 months after chemotherapy. Before chemotherapy, sperm DNA damage was higher in the cancer group than in community volunteers; this damage was increased
MALE INFERTILITY
2281
further at 6 months and remained elevated 24 months after treatment. Conclusion(s): Sperm generated after chemotherapy maintain a significant degree of chromatin damage. Therefore, survivors of testicular cancer and HL are at risk of having abnormal reproductive outcome. Proper counseling to these patients on reproductive risks and fertility preservation before chemotherapy is recommended. Editorial Comment: It is well established that having cancer harms sperm DNA, and chemotherapy hurts it more. Although freezing before chemotherapy saves sperm, many men with cancer still unfortunately do not choose this option. The question that patients want answered is, when is it safe to use sperm? These investigators demonstrate that sperm DNA damage persists for at least 2 years after treatment. We still do not have a time limit for chemotherapy after which it is safe to use sperm, making it imperative to encourage as many men as possible to cryopreserve sperm before treatment. Craig Niederberger, M.D.
Association of Cystic Fibrosis Genetic Modifiers With Congenital Bilateral Absence of the Vas Deferens V. Havasi, S. M. Rowe, P. N. Kolettis, D. Dayangac, A. Sahin, A. Grangeia, F. Carvalho, A. Barros, M. Sousa, L. Bassas, T. Casals and E. J. Sorscher Department of Medicine and Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama Fertil Steril 2010; 94: 2122–2127.
Objective: To investigate whether genetic modifiers of cystic fibrosis (CF) lung disease also predispose to congenital bilateral absence of the vas deferens (CBAVD) in association with cystic fibrosis transmembrane conductance regulator (CFTR) mutations. We tested the hypothesis that polymorphisms of transforming growth factor (TGF)-1 (rs 1982073, rs 1800471) and endothelin receptor type A (EDNRA) (rs 5335, rs 1801708) are associated with the CBAVD phenotype. Design: Genotyping of subjects with clinical CBAVD. Setting: Outpatient and hospital-based clinical evaluation. Patient(s): DNA samples from 80 subjects with CBAVD and 51 healthy male controls from various regions of Europe. This is one of the largest genetic studies of this disease to date. Intervention(s): None. Main Outcome Measure(s): Genotype analysis. Result(s): For single nucleotide polymorphism (SNP) rs 5335, we found increased frequency of the CC genotype among subjects with CBAVD. The difference was significant among Turkish patients versus controls (45.2% vs. 19.4%), and between all cases versus controls (36% vs. 15.7%). No associations between CBAVD penetrance and polymorphisms rs 1982073, rs 1800471, or rs 1801708 were observed. Conclusion(s): Our findings indicate that endothelin receptor type A polymorphism rs 5335 may be associated with CBAVD penetrance. To our knowledge, this is the first study to investigate genetic modifiers relevant to CBAVD. Editorial Comment: The human genome was sequenced 8 years ago, and we are only beginning to understand how it and we work. Even when we do know the genes it contains, the real labor will then begin, consisting of figuring out how genes coordinate in complex systems in health and disease. These authors sought genetic modifiers of cystic fibrosis in penetrance of congenital bilateral absence of the vas deferens, and observed a relationship between an endothelin receptor A polymorphism and CBAVD in men in Spain, Turkey and Portugal. As our understanding of the interrelationships between genes expands, we can expect more pieces of our genetic puzzles to fall into place, and perhaps eventually to have better means to counsel and treat our patients. Craig Niederberger, M.D.
MALE INFERTILITY
in oligozoospermic patients were AZFc deletions. Seven hundred eighteen patients underwent microdissection TESE, including 41 with microdeletions. Microdissection TESE failed in all patients with AZFa, AZFb, AZFb⫹c, and complete Yq deletions. Sperm were retrieved in 15/21 AZFc deleted patients (71.4%). The presence of an AZFc deletion was associated with increased likelihood of sperm retrieval when compared with the 48.8% retrieval rate in 385 idiopathically azoospermic men who consecutively underwent microdissection TESE at our institution during the study period. Clinical pregnancy was achieved in 10/15 azoospermic AZFc deleted patients for whom sperm were successfully retrieved. Conclusion(s): Of azoospermic and severely oligozoospermic American men, 10% harbor Y microdeletions that alter prognosis for surgical sperm retrieval and are vertically transmissible. Y microdeletion testing is essential for genetic and preoperative counseling in these patients. Editorial Comment: The usefulness of Y chromosomal microdeletion testing is twofold. If positive, you can counsel your patient that he will transmit it to male offspring, and if, as these authors observe, it is an AZFa, AZFb, AZFbⴙc or complete Yq deletion, the chance of retrieving sperm by extraction is diminishingly small, probably zero. A problem arises when the test is negative, which it most often is. We are not currently screening for the likely hundreds of genes involved in male reproduction because we do not yet know what they are. Consequently we must counsel all of our patients that the cause of their reproductive issues may be genetic, and that they must consider the possibility of transmission of unknown genetic mutations to offspring with artificial reproductive techniques. The problem with the emphatic statement that “Y microdeletion testing is essential for genetic and preoperative counseling” in patients with azoospermia and severe oligospermia is that patients need to be counseled about possible transmission of genetic mutations regardless of the results. Also, the likelihood of finding an AZFa, AZFb, AZFbⴙc or complete Yq deletion, where preoperative counseling actually matters, is low and varies greatly among geographic regions. Thus, the cost/benefit analysis must be entertained by an individual physician in his or her own practice. A better conclusion would encourage physicians to determine the incidence of AZFa, AZFb, AZFbⴙc or complete Yq deletions in their own practices, and to speak openly with patients about implications of testing based on regionally derived data. Craig Niederberger, M.D.
Re: Impact of Chemotherapeutics and Advanced Testicular Cancer or Hodgkin Lymphoma on Sperm Deoxyribonucleic Acid Integrity C. O’Flaherty, B. F. Hales, P. Chan and B. Robaire Department of Pharmacology and Therapeutics, McGill University Health Centre, Montreal, Quebec, Canada Fertil Steril 2010; 94: 1374 –1379.
Objective: To determine the impact of combination chemotherapy on the quality of newly generated spermatozoa from patients with advanced testicular cancer and patients with Hodgkin lymphoma (HL). Design: Prospective longitudinal study. Setting: Academic facility. Patient(s): Patients with newly diagnosed metastatic testicular cancer and with HL that required chemotherapy were compared with age-matched healthy community volunteers. Intervention(s): None. Main Outcome Measure(s): Semen parameters, hormone levels, testis volume, and presence of sperm DNA strand breaks in patients with cancer and in healthy community volunteers were compared before and after the patients’ chemotherapy at 6, 12, 18, and 24 months. Result(s): Before chemotherapy, both cancer groups had poorer semen quality compared with community volunteers. Among patients with testicular cancer and HL, 67% and 60%, respectively, had ⬍5x10(6) sperm/mL at 6 months after chemotherapy. At 24 months, 60% and 57% of patients with testicular cancer and HL, respectively, had normal sperm concentrations. Level of FSH was significantly higher in the cancer group compared with community volunteers at 6 to 12 months after chemotherapy. Before chemotherapy, sperm DNA damage was higher in the cancer group than in community volunteers; this damage was increased
MALE INFERTILITY
2281
further at 6 months and remained elevated 24 months after treatment. Conclusion(s): Sperm generated after chemotherapy maintain a significant degree of chromatin damage. Therefore, survivors of testicular cancer and HL are at risk of having abnormal reproductive outcome. Proper counseling to these patients on reproductive risks and fertility preservation before chemotherapy is recommended. Editorial Comment: It is well established that having cancer harms sperm DNA, and chemotherapy hurts it more. Although freezing before chemotherapy saves sperm, many men with cancer still unfortunately do not choose this option. The question that patients want answered is, when is it safe to use sperm? These investigators demonstrate that sperm DNA damage persists for at least 2 years after treatment. We still do not have a time limit for chemotherapy after which it is safe to use sperm, making it imperative to encourage as many men as possible to cryopreserve sperm before treatment. Craig Niederberger, M.D.
Association of Cystic Fibrosis Genetic Modifiers With Congenital Bilateral Absence of the Vas Deferens V. Havasi, S. M. Rowe, P. N. Kolettis, D. Dayangac, A. Sahin, A. Grangeia, F. Carvalho, A. Barros, M. Sousa, L. Bassas, T. Casals and E. J. Sorscher Department of Medicine and Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama Fertil Steril 2010; 94: 2122–2127.
Objective: To investigate whether genetic modifiers of cystic fibrosis (CF) lung disease also predispose to congenital bilateral absence of the vas deferens (CBAVD) in association with cystic fibrosis transmembrane conductance regulator (CFTR) mutations. We tested the hypothesis that polymorphisms of transforming growth factor (TGF)-1 (rs 1982073, rs 1800471) and endothelin receptor type A (EDNRA) (rs 5335, rs 1801708) are associated with the CBAVD phenotype. Design: Genotyping of subjects with clinical CBAVD. Setting: Outpatient and hospital-based clinical evaluation. Patient(s): DNA samples from 80 subjects with CBAVD and 51 healthy male controls from various regions of Europe. This is one of the largest genetic studies of this disease to date. Intervention(s): None. Main Outcome Measure(s): Genotype analysis. Result(s): For single nucleotide polymorphism (SNP) rs 5335, we found increased frequency of the CC genotype among subjects with CBAVD. The difference was significant among Turkish patients versus controls (45.2% vs. 19.4%), and between all cases versus controls (36% vs. 15.7%). No associations between CBAVD penetrance and polymorphisms rs 1982073, rs 1800471, or rs 1801708 were observed. Conclusion(s): Our findings indicate that endothelin receptor type A polymorphism rs 5335 may be associated with CBAVD penetrance. To our knowledge, this is the first study to investigate genetic modifiers relevant to CBAVD. Editorial Comment: The human genome was sequenced 8 years ago, and we are only beginning to understand how it and we work. Even when we do know the genes it contains, the real labor will then begin, consisting of figuring out how genes coordinate in complex systems in health and disease. These authors sought genetic modifiers of cystic fibrosis in penetrance of congenital bilateral absence of the vas deferens, and observed a relationship between an endothelin receptor A polymorphism and CBAVD in men in Spain, Turkey and Portugal. As our understanding of the interrelationships between genes expands, we can expect more pieces of our genetic puzzles to fall into place, and perhaps eventually to have better means to counsel and treat our patients. Craig Niederberger, M.D.