- Email: [email protected]
Male Infertility
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to end-of-treatment improvement in the sildenafil groups vs placebo was greater (P⬍0.001) for the perpatient proportion (PPP) of ‘yes’ responses to the Sexual Encounter Profile question 3 (SEP3: successful intercourse (primary outcome)) (odds ratio (OR)⫽3.2 (trial 1), 7.6 (trial 2) and 5.6 (pooled data)); PPP of erection hardness score 4 (EHS 4, completely hard and fully rigid) (OR⫽6.2 (trial 1) and 10.9 (trial 2)); scores on the International Index of Erectile Function; and other EHS and SEP outcomes. Two to three times as many men were satisfied with sildenafil vs placebo treatment (Erectile Dysfunction Inventory of Treatment Satisfaction Index ⬎50). Thus, responsiveness to 100 mg sildenafil may persist for 8 h postdose in men with mild to moderate ED. Editorial Comment: These data suggest that some men continue to receive benefit from sildenafil 8 hours after a 100 mg dose. This finding is helpful when counseling patients, because it may allow for an extended window of sexual activity beyond the currently held belief of a 4-hour window of activity for sildenafil. Allen Seftel, M.D.
Treatment of Symptomatic Androgen Deficiency: Results From the Boston Area Community Health Survey S. A. Hall, A. B. Araujo, G. R. Esche, R. E. Williams, R. V. Clark, T. G. Travison and J. B. McKinlay, New England Research Institutes, Watertown, Massachusetts Arch Intern Med 2008; 168: 1070 –1076. Background: Despite the aging of the US population and increasing sales of prescription testosterone, treatment patterns for androgen deficiency (AD) are poorly understood. We describe patterns and correlates of testosterone treatment in community-dwelling men. Methods: The Boston Area Community Health Survey is an observational study of a population-based random sample of racially and ethnically diverse men representative of Boston, Massachusetts. Data collected by in-person interview from April 2002 to June 2005 included health status, socioeconomic status, access to medical care, and use of prescription medications. A venous blood sample was collected. The operational definition of untreated AD was serum total testosterone level less than 300 ng/dL (to convert to nanomoles per liter, multiply by 0.0347) and free testosterone level less than 5 ng/dL, and the presence of at least 1 specific symptom (low libido, erectile dysfunction, or osteoporosis) or 2 or more less-specific symptoms (sleep disturbance, depressed mood, lethargy, or diminished physical performance) and not using prescription testosterone. Any man who was using testosterone was considered to have treated AD. Results: Data were available for 1486 Boston Area Community Health Survey participants (mean age, 46.4 years; age range, 30 –79 years). A total of 5.5% (95% confidence interval, 3.5– 8.5) men met the criteria for having untreated, symptomatic AD, and 0.8% (95% confidence interval, 0.4 –1.4) met the criteria for having treated AD. Considering all cases, the proportion treated was 12.2%. Men with untreated AD seemed to have adequate access to care. Conclusions: Under our assumptions, a large majority (87.8%) of 97 men in our groups with AD were not receiving treatment despite adequate access to care. The reasons for this are unknown but could be due to unrecognized AD or unwillingness to prescribe testosterone therapy. Editorial Comment: These are intriguing data. The average patient age was 46.2 years, a rather youngish cohort. Of the men 5.5% met the criteria for untreated AD. Only 12.2% of men with AD were treated. This finding may represent under recognition of AD as a bona fide disease entity, and suggests that education in this area is in order. Future studies elucidating the educational deficits and offering suggestions for educational initiatives will be of value. Allen Seftel, M.D.
MALE INFERTILITY Radiofrequency Electromagnetic Fields; Male Infertility and Sex Ratio of Offspring V. Baste, T. Riise and B. E. Moen, Department of Public Health and Primary Health Care, Section for Occupational Medicine, UNIFOB AS, University of Bergen, Bergen, Norway Eur J Epidemiol 2008; 23: 369. Concern is growing about exposure to electromagnetic fields and male reproductive health. The authors performed a cross-sectional study among military men employed in the Royal Norwegian Navy, including
2136
MALE INFERTILITY information about work close to equipment emitting radiofrequency electromagnetic fields, one-year infertility, children and sex of the offspring. Among 10,497 respondents, 22% had worked close to high-frequency aerials to a “high” or “very high” degree. Infertility increased significantly along with increasing selfreported exposure to radiofrequency electromagnetic fields. In a logistic regression, odds ratio (OR) for infertility among those who had worked closer than 10 m from high-frequency aerials to a “very high” degree relative to those who reported no work near high-frequency aerials was 1.86 (95% confidence interval (CI): 1.46 –2.37), adjusted for age, smoking habits, alcohol consumption and exposure to organic solvents, welding and lead. Similar adjusted OR for those exposed to a “high”, “some” and “low” degree were 1.93 (95% CI: 1.55–2.40), 1.52 (95% CI: 1.25–1.84), and 1.39 (95% CI: 1.15–1.68), respectively. In all age groups there were significant linear trends with higher prevalence of involuntary childlessness with higher self-reported exposure to radiofrequency fields. However, the degree of exposure to radiofrequency radiation and the number of children were not associated. For self-reported exposure both to high-frequency aerials and communication equipment there were significant linear trends with lower ratio of boys to girls at birth when the father reported a higher degree of radiofrequency electromagnetic exposure. Editorial Comment: Clinical scientists previously reported observations potentially linking radio frequency electromagnetic field exposure to indicators of male infertility. The secondary sex ratio, or ratio of boys to girls born, generally favors boys. If this ratio is changing, it may reveal reproductive hazards. These authors studied the relationship between radio frequency electromagnetic radiation exposure by correlating the secondary sex ratio of offspring and failure to impregnate reported by questionnaire for 10,497 men in the Royal Norwegian Navy. Sailors were classified into groups, including those who worked within 10 meters of high frequency aerials, those within 3 meters of communication equipment and those within 5 meters of radar. In their analysis the investigators excluded the possible confounders of exposure to organic solvents, welding, lead, age, smoking and alcohol consumption. The authors observed linear trends between infertility and radio frequency exposure, and between a decrease in the secondary sex ratio and radio frequency electromagnetic exposure. Although the statistically significant patterns of the observed trends were imperfect, these data derived from expectedly high radio frequency electromagnetic exposure suggest that such exposure may affect male reproductive outcomes. Craig Niederberger, M.D.
Association of Secondary Sex Ratio With Smoking and Parity N. G. Beratis, A. Asimacopoulou and A. Varvarigou, Department of Pediatrics, General University Hospital of Patras, University of Patras Medical School, Rio, Patras, Greece Fertil Steril 2008; 89: 662– 667. Objective: To assess the sex ratio in offspring of smoking and nonsmoking mothers in relationship to parity. Design: Prospective study. Setting: University hospital. Patient(s): The authors studied 2,108 term singleton neonates born between 1993 and 2002, 665 from smoking mothers and 1,443 from nonsmoking mothers. Intervention(s): A prospective recording of maternal age, parity and smoking status, and gender of neonates delivered over a 10-year period. Main Outcome Measure(s): Secondary sex ratio in regard to maternal smoking and parity. Result(s): The offspring sex ratio in the total sample studied was 1.09; in the offspring of smoking and nonsmoking mothers, it was 1.26 and 1.03, respectively, a statistically significant difference. In the offspring of smoking women who had parity 1, 2, and ⬎or⫽3, it was 1.47, 1.35, and 0.92, whereas in those of nonsmoking women, it was 1.04, 1.00, and 1.03, respectively (the differences of the parity 1 and 2 groups between the offspring of smoking and nonsmoking mothers were statistically significant). Logistic regression analysis showed that the possibility of a boy being delivered by a mother who smoked was significantly greater in primiparous women than in women who had parity ⬎or⫽3, independent of the maternal age. Conversely, parity did not affect significantly the sex ratio in the offspring of nonsmoking women. Conclusion(s): The findings suggest that among women who smoked, significantly more male than female offspring are born from primiparous women, whereas women who had parity ⬎or⫽3 gave birth to more female offspring; biparous women give birth to significantly more male offspring, but the offspring sex ratio declined with the number of cigarettes when the mothers smoked ⬎or⫽10 cigarettes per day. Editorial Comment: The secondary sex ratio typically decreases in the face of toxicity. These investigators studied the effect of maternal cigarette smoking on the secondary sex ratio in 2,108 children born to smoking mothers and 1,443 from nonsmoking mothers. Seemingly paradoxically, the authors observed that the secondary sex ratio was highest in mothers bearing their first child, with nearly 3 boys born for every 2 girls. The effect of smoking on the secondary
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sex ratio decreased with parity, and for mothers having borne 2 or more previous children the secondary sex ratio was less than 1.0, favoring more girls born than boys. No relationship was observed between parity and the secondary sex ratio for nonsmoking mothers. While unidentified confounders may account for the observed relationship between smoking, parity and secondary sex ratio, one can imagine that given the desire of many prospective parents for boys, an unhealthy perception may propagate that if a mother wants a firstborn son, she should smoke cigarettes. As physicians, we should guard against such a perception. Craig Niederberger, M.D.
Paternal Age and Mortality in Children J. L. Zhu, M. Vestergaard, K. M. Madsen and J. Olsen, Danish Epidemiology Science Centre, University of Aarhus, Aarhus, Denmark Eur J Epidemiol 2008; 23: 443– 447. Background: Since paternal age correlates with some diseases that have a high case-fatality, a paternal age effect on offspring’s survival is expected but unsettled. We examined the association between paternal age and mortality in children in a large population-based cohort taking maternal age and socioeconomic factors into account. Methods: From the Danish Fertility Database (1980 –1996), we identified 102,879 couples and their firstborn singleton children. Information on childhood death (N ⫽ 831) was obtained by linking the cohort to the nationwide register on cause of death (1980 –1998). Results: We observed a U-shaped association between paternal age and the overall mortality rate in children up to 18 years of age. Adjustment for maternal age and other confounders reduced the mortality rate ratio (MRR) for children of younger fathers but not for children of older fathers. Compared with children of fathers aged between 25 and 29 years, the adjusted MRR was 1.77 (95% confidence interval 1.28 –2.45) for children of fathers aged between 45 and 49 years and 1.59 (1.03–2.46) for children of fathers aged 50 years or more. The cause-specific MRRs were highest for congenital malformations [2.35 (1.42–3.88)] and injury or poisoning [3.43 (1.49 –7.92)] for children of fathers aged 45 years or more. Conclusion: Our data revealed a higher mortality in offspring of fathers aged 45 years or more that lasted into adulthood. This adds to the cumulating evidence on adverse effects of advanced paternal age in procreation. Editorial Comment: The effect of male age on offspring is much debated. Investigators have proposed relationships between advancing paternal age and autism, congenital malformations, cancer and other diseases. These authors studied the effect of paternal age on childhood mortality in a large Danish database from which information on childhood death was available in more than 800 cases. They classified causes of death into 5 groups, and excluded possible confounders of maternal age, parity, education, income, country of origin and calendar year in their analysis. The authors observed the highest cause specific mortality rate ratio for fathers older than 45 years to be that for congenital malformations, which would be expected to have a genetic basis, and death by injury or poisoning, which would not. While this study points in the direction of a potentially adverse effect of male aging on the genetics of offspring, it also reminds us that far more than genetics determines how offspring fare. Craig Niederberger, M.D.
Age-Related Increase of Reactive Oxygen Species in Neat Semen in Healthy Fertile Men M. Cocuzza, K. S. Athayde, A. Agarwal, R. Sharma, R. Pagani, A. M. Lucon, M. Srougi and J. Hallak, Department of Urology, University of Sao Paulo, Sao Paulo, Brazil Urology 2008; 71: 490 – 494. Objectives: The effects of advancing paternal age on the male reproductive system are well known, but its effects on fecundity remain controversial. Although oxidative stress is associated with poor semen quality and function, a relationship with advancing male age has not been established. The objective of this study was to analyze the relationship between male age and seminal reactive oxygen species (ROS) levels in men presenting for voluntary sterilization. Methods: We prospectively evaluated 98 fertile men who were candidates for vasectomy. These were divided into 2 age groups: less than 40 years (n ⫽ 78) and 40 or more years (n ⫽ 20). We used 46 infertile patients as positive controls. Standard semen analysis, seminal leukocyte count and ROS levels were measured in all samples. Fertile men with leukocytospermia were
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MALE INFERTILITY excluded. Results: The mean age of the men was 35.1 ⫹/⫺ 5.6 years. Men 40 years and older had significantly higher ROS levels compared with younger men (P ⬍0.001). We observed a positive correlation between seminal ROS levels and age (r ⫽ 0.20; P ⫽ 0.040). In addition, ROS was negatively correlated with sperm concentration (r ⫽ ⫺0.48; P ⬍0.001) and motility (r ⫽ ⫺0.21; P ⫽ 0.030). Conclusions: Reactive oxygen species levels are significant higher in seminal ejaculates of healthy fertile men older than 40 years. ROS levels in whole ejaculate are significantly correlated to age among fertile men. Because ROS are clearly implicated in the pathogenesis of male infertility, these data suggest that delayed fatherhood may reduce the chances of pregnancy as men become progressively less fertile with age. Editorial Comment: Woe to the aging male. Whereas it once seemed that bulk sperm parameters declined slightly if at all as men aged, with modern tools and databases investigators are discovering that sperm DNA integrity may degrade and the mortality of offspring may increase as potential fathers become older. As evidence accumulates that the presence of ROS may hamper sperm function, these authors correlated male age to seminal ROS in 98 fertile men presenting for vasectomy and 46 infertile men. Seminal ROS levels increased as men aged, and as previously observed, infertile men had significantly higher ROS levels than fertile ones. While it remains to be seen whether the mild increase in seminal ROS levels in men older than 40 substantially hampers their ability to father offspring, increasing ROS in the semen likely does not help. Craig Niederberger, M.D.
Seminal Anti-Müllerian Hormone Level is a Marker of Spermatogenic Response During Long-Term Gonadotropin Therapy in Male Hypogonadotropic Hypogonadism A. A. Sinisi, D. Esposito, L. Maione, M. C. Quinto, D. Visconti, A. De Bellis, A. Bellastella, G. Conzo and G. Bellastella, Endocrinology and Medical Andrology Section, Department of Clinical and Experimental Medicine and Surgery, Seconda Universita di Napoli, Napoli, Italy Hum Reprod 2008; 23: 1029 –1034. Background: In adult men, anti-Müllerian hormone (AMH) levels are higher in semen than in serum, but the significance and control of its seminal secretion are still unknown. This study evaluated seminal and serum AMH levels during long-term gonadotropin therapy in men with hypogonadotropic hypogonadism (HH). Methods: A total of 20 men with never treated prepubertal-onset HH received i.m. hCG to normalize testosterone (T) and induce puberty. Afterwards, 11 of them, requiring fertility, were treated with HCG plus recombinant FSH (rFSH) (75 IU) twice a week, whereas 9 continued to receive hCG alone for 12 months. Before and during therapy, serum AMH, inhibin B and T levels were assessed. Semen samples were also collected during therapy for sperm count and seminal AMH assay. Results: HCG alone decreased basal high serum AMH and stimulated T and inhibin B levels. rFSH plus hCG increased seminal AMH levels, which were consequently significantly higher than with hCG alone, and positively correlated to sperm densities and testicular volumes at 3 and 12 months (P ⬍0.001). Conclusions: Our data demonstrate that rFSH, added to hCG, stimulates seminal AMH and spermatogenesis in HH. Thus, seminal AMH levels are under T and FSH control and are closely related to progression of spermatogenesis. Our results also suggest that an early seminal AMH increase may be a marker of good future response to gonadotropin therapy in HH. Editorial Comment: With the exception of antisperm antibodies and sperm itself, most of the factors clinicians assess in evaluating male reproductive function are derived from the blood. Yet many proteins and hormones are expressed in the seminiferous epithelium and epididymis. Anti-mullerian hormone is produced by Sertoli cells, and is present in blood and semen. These investigators sought to determine if seminal AMH levels predicted outcomes of men undergoing treatment for hypogonadotropic hypogonadism. They administered human chorionic gonadotropin to 20 men and recombinant follicle-stimulating hormone to 11 of the 20, and assessed semen parameters, seminal and serum AMH, serum testosterone and inhibin B. The authors observed an expected increase in seminal AMH when adding rFSH, since follicle-stimulating hormone stimulates Sertoli cells. Interestingly, they found that sperm density and testis volume after treatment were correlated with seminal AMH levels at month 3, providing a potential means of forecasting treatment outcomes. This study reminds us that the semen itself is a fertile source of assayable factors that may be useful in evaluating male reproductive function. Craig Niederberger, M.D.
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to end-of-treatment improvement in the sildenafil groups vs placebo was greater (P⬍0.001) for the perpatient proportion (PPP) of ‘yes’ responses to the Sexual Encounter Profile question 3 (SEP3: successful intercourse (primary outcome)) (odds ratio (OR)⫽3.2 (trial 1), 7.6 (trial 2) and 5.6 (pooled data)); PPP of erection hardness score 4 (EHS 4, completely hard and fully rigid) (OR⫽6.2 (trial 1) and 10.9 (trial 2)); scores on the International Index of Erectile Function; and other EHS and SEP outcomes. Two to three times as many men were satisfied with sildenafil vs placebo treatment (Erectile Dysfunction Inventory of Treatment Satisfaction Index ⬎50). Thus, responsiveness to 100 mg sildenafil may persist for 8 h postdose in men with mild to moderate ED. Editorial Comment: These data suggest that some men continue to receive benefit from sildenafil 8 hours after a 100 mg dose. This finding is helpful when counseling patients, because it may allow for an extended window of sexual activity beyond the currently held belief of a 4-hour window of activity for sildenafil. Allen Seftel, M.D.
Treatment of Symptomatic Androgen Deficiency: Results From the Boston Area Community Health Survey S. A. Hall, A. B. Araujo, G. R. Esche, R. E. Williams, R. V. Clark, T. G. Travison and J. B. McKinlay, New England Research Institutes, Watertown, Massachusetts Arch Intern Med 2008; 168: 1070 –1076. Background: Despite the aging of the US population and increasing sales of prescription testosterone, treatment patterns for androgen deficiency (AD) are poorly understood. We describe patterns and correlates of testosterone treatment in community-dwelling men. Methods: The Boston Area Community Health Survey is an observational study of a population-based random sample of racially and ethnically diverse men representative of Boston, Massachusetts. Data collected by in-person interview from April 2002 to June 2005 included health status, socioeconomic status, access to medical care, and use of prescription medications. A venous blood sample was collected. The operational definition of untreated AD was serum total testosterone level less than 300 ng/dL (to convert to nanomoles per liter, multiply by 0.0347) and free testosterone level less than 5 ng/dL, and the presence of at least 1 specific symptom (low libido, erectile dysfunction, or osteoporosis) or 2 or more less-specific symptoms (sleep disturbance, depressed mood, lethargy, or diminished physical performance) and not using prescription testosterone. Any man who was using testosterone was considered to have treated AD. Results: Data were available for 1486 Boston Area Community Health Survey participants (mean age, 46.4 years; age range, 30 –79 years). A total of 5.5% (95% confidence interval, 3.5– 8.5) men met the criteria for having untreated, symptomatic AD, and 0.8% (95% confidence interval, 0.4 –1.4) met the criteria for having treated AD. Considering all cases, the proportion treated was 12.2%. Men with untreated AD seemed to have adequate access to care. Conclusions: Under our assumptions, a large majority (87.8%) of 97 men in our groups with AD were not receiving treatment despite adequate access to care. The reasons for this are unknown but could be due to unrecognized AD or unwillingness to prescribe testosterone therapy. Editorial Comment: These are intriguing data. The average patient age was 46.2 years, a rather youngish cohort. Of the men 5.5% met the criteria for untreated AD. Only 12.2% of men with AD were treated. This finding may represent under recognition of AD as a bona fide disease entity, and suggests that education in this area is in order. Future studies elucidating the educational deficits and offering suggestions for educational initiatives will be of value. Allen Seftel, M.D.
MALE INFERTILITY Radiofrequency Electromagnetic Fields; Male Infertility and Sex Ratio of Offspring V. Baste, T. Riise and B. E. Moen, Department of Public Health and Primary Health Care, Section for Occupational Medicine, UNIFOB AS, University of Bergen, Bergen, Norway Eur J Epidemiol 2008; 23: 369. Concern is growing about exposure to electromagnetic fields and male reproductive health. The authors performed a cross-sectional study among military men employed in the Royal Norwegian Navy, including
2136
MALE INFERTILITY information about work close to equipment emitting radiofrequency electromagnetic fields, one-year infertility, children and sex of the offspring. Among 10,497 respondents, 22% had worked close to high-frequency aerials to a “high” or “very high” degree. Infertility increased significantly along with increasing selfreported exposure to radiofrequency electromagnetic fields. In a logistic regression, odds ratio (OR) for infertility among those who had worked closer than 10 m from high-frequency aerials to a “very high” degree relative to those who reported no work near high-frequency aerials was 1.86 (95% confidence interval (CI): 1.46 –2.37), adjusted for age, smoking habits, alcohol consumption and exposure to organic solvents, welding and lead. Similar adjusted OR for those exposed to a “high”, “some” and “low” degree were 1.93 (95% CI: 1.55–2.40), 1.52 (95% CI: 1.25–1.84), and 1.39 (95% CI: 1.15–1.68), respectively. In all age groups there were significant linear trends with higher prevalence of involuntary childlessness with higher self-reported exposure to radiofrequency fields. However, the degree of exposure to radiofrequency radiation and the number of children were not associated. For self-reported exposure both to high-frequency aerials and communication equipment there were significant linear trends with lower ratio of boys to girls at birth when the father reported a higher degree of radiofrequency electromagnetic exposure. Editorial Comment: Clinical scientists previously reported observations potentially linking radio frequency electromagnetic field exposure to indicators of male infertility. The secondary sex ratio, or ratio of boys to girls born, generally favors boys. If this ratio is changing, it may reveal reproductive hazards. These authors studied the relationship between radio frequency electromagnetic radiation exposure by correlating the secondary sex ratio of offspring and failure to impregnate reported by questionnaire for 10,497 men in the Royal Norwegian Navy. Sailors were classified into groups, including those who worked within 10 meters of high frequency aerials, those within 3 meters of communication equipment and those within 5 meters of radar. In their analysis the investigators excluded the possible confounders of exposure to organic solvents, welding, lead, age, smoking and alcohol consumption. The authors observed linear trends between infertility and radio frequency exposure, and between a decrease in the secondary sex ratio and radio frequency electromagnetic exposure. Although the statistically significant patterns of the observed trends were imperfect, these data derived from expectedly high radio frequency electromagnetic exposure suggest that such exposure may affect male reproductive outcomes. Craig Niederberger, M.D.
Association of Secondary Sex Ratio With Smoking and Parity N. G. Beratis, A. Asimacopoulou and A. Varvarigou, Department of Pediatrics, General University Hospital of Patras, University of Patras Medical School, Rio, Patras, Greece Fertil Steril 2008; 89: 662– 667. Objective: To assess the sex ratio in offspring of smoking and nonsmoking mothers in relationship to parity. Design: Prospective study. Setting: University hospital. Patient(s): The authors studied 2,108 term singleton neonates born between 1993 and 2002, 665 from smoking mothers and 1,443 from nonsmoking mothers. Intervention(s): A prospective recording of maternal age, parity and smoking status, and gender of neonates delivered over a 10-year period. Main Outcome Measure(s): Secondary sex ratio in regard to maternal smoking and parity. Result(s): The offspring sex ratio in the total sample studied was 1.09; in the offspring of smoking and nonsmoking mothers, it was 1.26 and 1.03, respectively, a statistically significant difference. In the offspring of smoking women who had parity 1, 2, and ⬎or⫽3, it was 1.47, 1.35, and 0.92, whereas in those of nonsmoking women, it was 1.04, 1.00, and 1.03, respectively (the differences of the parity 1 and 2 groups between the offspring of smoking and nonsmoking mothers were statistically significant). Logistic regression analysis showed that the possibility of a boy being delivered by a mother who smoked was significantly greater in primiparous women than in women who had parity ⬎or⫽3, independent of the maternal age. Conversely, parity did not affect significantly the sex ratio in the offspring of nonsmoking women. Conclusion(s): The findings suggest that among women who smoked, significantly more male than female offspring are born from primiparous women, whereas women who had parity ⬎or⫽3 gave birth to more female offspring; biparous women give birth to significantly more male offspring, but the offspring sex ratio declined with the number of cigarettes when the mothers smoked ⬎or⫽10 cigarettes per day. Editorial Comment: The secondary sex ratio typically decreases in the face of toxicity. These investigators studied the effect of maternal cigarette smoking on the secondary sex ratio in 2,108 children born to smoking mothers and 1,443 from nonsmoking mothers. Seemingly paradoxically, the authors observed that the secondary sex ratio was highest in mothers bearing their first child, with nearly 3 boys born for every 2 girls. The effect of smoking on the secondary
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sex ratio decreased with parity, and for mothers having borne 2 or more previous children the secondary sex ratio was less than 1.0, favoring more girls born than boys. No relationship was observed between parity and the secondary sex ratio for nonsmoking mothers. While unidentified confounders may account for the observed relationship between smoking, parity and secondary sex ratio, one can imagine that given the desire of many prospective parents for boys, an unhealthy perception may propagate that if a mother wants a firstborn son, she should smoke cigarettes. As physicians, we should guard against such a perception. Craig Niederberger, M.D.
Paternal Age and Mortality in Children J. L. Zhu, M. Vestergaard, K. M. Madsen and J. Olsen, Danish Epidemiology Science Centre, University of Aarhus, Aarhus, Denmark Eur J Epidemiol 2008; 23: 443– 447. Background: Since paternal age correlates with some diseases that have a high case-fatality, a paternal age effect on offspring’s survival is expected but unsettled. We examined the association between paternal age and mortality in children in a large population-based cohort taking maternal age and socioeconomic factors into account. Methods: From the Danish Fertility Database (1980 –1996), we identified 102,879 couples and their firstborn singleton children. Information on childhood death (N ⫽ 831) was obtained by linking the cohort to the nationwide register on cause of death (1980 –1998). Results: We observed a U-shaped association between paternal age and the overall mortality rate in children up to 18 years of age. Adjustment for maternal age and other confounders reduced the mortality rate ratio (MRR) for children of younger fathers but not for children of older fathers. Compared with children of fathers aged between 25 and 29 years, the adjusted MRR was 1.77 (95% confidence interval 1.28 –2.45) for children of fathers aged between 45 and 49 years and 1.59 (1.03–2.46) for children of fathers aged 50 years or more. The cause-specific MRRs were highest for congenital malformations [2.35 (1.42–3.88)] and injury or poisoning [3.43 (1.49 –7.92)] for children of fathers aged 45 years or more. Conclusion: Our data revealed a higher mortality in offspring of fathers aged 45 years or more that lasted into adulthood. This adds to the cumulating evidence on adverse effects of advanced paternal age in procreation. Editorial Comment: The effect of male age on offspring is much debated. Investigators have proposed relationships between advancing paternal age and autism, congenital malformations, cancer and other diseases. These authors studied the effect of paternal age on childhood mortality in a large Danish database from which information on childhood death was available in more than 800 cases. They classified causes of death into 5 groups, and excluded possible confounders of maternal age, parity, education, income, country of origin and calendar year in their analysis. The authors observed the highest cause specific mortality rate ratio for fathers older than 45 years to be that for congenital malformations, which would be expected to have a genetic basis, and death by injury or poisoning, which would not. While this study points in the direction of a potentially adverse effect of male aging on the genetics of offspring, it also reminds us that far more than genetics determines how offspring fare. Craig Niederberger, M.D.
Age-Related Increase of Reactive Oxygen Species in Neat Semen in Healthy Fertile Men M. Cocuzza, K. S. Athayde, A. Agarwal, R. Sharma, R. Pagani, A. M. Lucon, M. Srougi and J. Hallak, Department of Urology, University of Sao Paulo, Sao Paulo, Brazil Urology 2008; 71: 490 – 494. Objectives: The effects of advancing paternal age on the male reproductive system are well known, but its effects on fecundity remain controversial. Although oxidative stress is associated with poor semen quality and function, a relationship with advancing male age has not been established. The objective of this study was to analyze the relationship between male age and seminal reactive oxygen species (ROS) levels in men presenting for voluntary sterilization. Methods: We prospectively evaluated 98 fertile men who were candidates for vasectomy. These were divided into 2 age groups: less than 40 years (n ⫽ 78) and 40 or more years (n ⫽ 20). We used 46 infertile patients as positive controls. Standard semen analysis, seminal leukocyte count and ROS levels were measured in all samples. Fertile men with leukocytospermia were
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MALE INFERTILITY excluded. Results: The mean age of the men was 35.1 ⫹/⫺ 5.6 years. Men 40 years and older had significantly higher ROS levels compared with younger men (P ⬍0.001). We observed a positive correlation between seminal ROS levels and age (r ⫽ 0.20; P ⫽ 0.040). In addition, ROS was negatively correlated with sperm concentration (r ⫽ ⫺0.48; P ⬍0.001) and motility (r ⫽ ⫺0.21; P ⫽ 0.030). Conclusions: Reactive oxygen species levels are significant higher in seminal ejaculates of healthy fertile men older than 40 years. ROS levels in whole ejaculate are significantly correlated to age among fertile men. Because ROS are clearly implicated in the pathogenesis of male infertility, these data suggest that delayed fatherhood may reduce the chances of pregnancy as men become progressively less fertile with age. Editorial Comment: Woe to the aging male. Whereas it once seemed that bulk sperm parameters declined slightly if at all as men aged, with modern tools and databases investigators are discovering that sperm DNA integrity may degrade and the mortality of offspring may increase as potential fathers become older. As evidence accumulates that the presence of ROS may hamper sperm function, these authors correlated male age to seminal ROS in 98 fertile men presenting for vasectomy and 46 infertile men. Seminal ROS levels increased as men aged, and as previously observed, infertile men had significantly higher ROS levels than fertile ones. While it remains to be seen whether the mild increase in seminal ROS levels in men older than 40 substantially hampers their ability to father offspring, increasing ROS in the semen likely does not help. Craig Niederberger, M.D.
Seminal Anti-Müllerian Hormone Level is a Marker of Spermatogenic Response During Long-Term Gonadotropin Therapy in Male Hypogonadotropic Hypogonadism A. A. Sinisi, D. Esposito, L. Maione, M. C. Quinto, D. Visconti, A. De Bellis, A. Bellastella, G. Conzo and G. Bellastella, Endocrinology and Medical Andrology Section, Department of Clinical and Experimental Medicine and Surgery, Seconda Universita di Napoli, Napoli, Italy Hum Reprod 2008; 23: 1029 –1034. Background: In adult men, anti-Müllerian hormone (AMH) levels are higher in semen than in serum, but the significance and control of its seminal secretion are still unknown. This study evaluated seminal and serum AMH levels during long-term gonadotropin therapy in men with hypogonadotropic hypogonadism (HH). Methods: A total of 20 men with never treated prepubertal-onset HH received i.m. hCG to normalize testosterone (T) and induce puberty. Afterwards, 11 of them, requiring fertility, were treated with HCG plus recombinant FSH (rFSH) (75 IU) twice a week, whereas 9 continued to receive hCG alone for 12 months. Before and during therapy, serum AMH, inhibin B and T levels were assessed. Semen samples were also collected during therapy for sperm count and seminal AMH assay. Results: HCG alone decreased basal high serum AMH and stimulated T and inhibin B levels. rFSH plus hCG increased seminal AMH levels, which were consequently significantly higher than with hCG alone, and positively correlated to sperm densities and testicular volumes at 3 and 12 months (P ⬍0.001). Conclusions: Our data demonstrate that rFSH, added to hCG, stimulates seminal AMH and spermatogenesis in HH. Thus, seminal AMH levels are under T and FSH control and are closely related to progression of spermatogenesis. Our results also suggest that an early seminal AMH increase may be a marker of good future response to gonadotropin therapy in HH. Editorial Comment: With the exception of antisperm antibodies and sperm itself, most of the factors clinicians assess in evaluating male reproductive function are derived from the blood. Yet many proteins and hormones are expressed in the seminiferous epithelium and epididymis. Anti-mullerian hormone is produced by Sertoli cells, and is present in blood and semen. These investigators sought to determine if seminal AMH levels predicted outcomes of men undergoing treatment for hypogonadotropic hypogonadism. They administered human chorionic gonadotropin to 20 men and recombinant follicle-stimulating hormone to 11 of the 20, and assessed semen parameters, seminal and serum AMH, serum testosterone and inhibin B. The authors observed an expected increase in seminal AMH when adding rFSH, since follicle-stimulating hormone stimulates Sertoli cells. Interestingly, they found that sperm density and testis volume after treatment were correlated with seminal AMH levels at month 3, providing a potential means of forecasting treatment outcomes. This study reminds us that the semen itself is a fertile source of assayable factors that may be useful in evaluating male reproductive function. Craig Niederberger, M.D.