Fertility and Aging Men An Introduction to the Male Biological Clock

Puneet Masson, Sarah M. Lambert, Peter N. Schlegel, and Harry Fisch

Data obtained in the past decade suggested a worldwide decline in male fertility. The increase in paternal age is both a personal problem for couples and a public health problem because of the simple fact that male fertility declines with age. Journal articles by Kidd and Ford demonstrate that men over the age of 35 are twice as likely to be infertile as men younger than 25. In addition, a study of couples undergoing fertility treatments found that the amount of time it takes for a man to achieve a pregnancy rises significantly with age.

The levels of sex hormones in men decline with age. The roughly 1% per year decline in testosterone levels after age 30 has been termed andropause, or ''symptomatic hypogonadism in the aging male.'' Rhoden and Morgentaler estimate that between 2 and 4 million men in the United States alone suffer from hypogonadism, but only 5% of men are getting treatment for their symptoms.

Although increasing maternal age has long been known to be associated with an increased incidence of birth defects, new data show that the age of the male does matter and the genetic quality of sperm does decline with age. Several studies have demonstrated that older men are at higher risk of fathering a child with various genetic diseases such as schizophrenia and Down Syndrome, to name a few. Additionally, there has been an increased risk of miscarriage with increasing paternal age.

This review discusses the relationship between advanced paternal age and male infertility. Continuing this dialogue will improve the sexual and reproductive health of aging males.

Introduction

Say ''biological clock,'' and most people immediately think, ''women.'' Female fertility, after all, ''strikes midnight'' with the cessation of menses. This occurs in association with distinct—and dramatic—declines in estrogen production. And as women age, the genetic quality of their eggs declines and the subsequent increased proportion of genetically damaged embryos leads to an increased risk of genetic problems in their offspring.

This triad of declining fertility, declining hormone levels, and increasing risk for genetic problems is what most people mean when they say ''biological clock.''

Until recently, that is. Although it is an idea that has not yet filtered down to the general public, we now know that men have biological clocks, too. And those clocks involve the same physiological triad experienced by women. Male fertility and male sex hormones do decline with age. And the genetic quality of sperm does decline, leading to an increased risk of genetic problems in offspring above and beyond any contributed by the female. The object of this review is to describe these features of male aging and, hence, to expand the notion of the ''biological clock'' to include both sexes.

Conceptions of Fertility

It is a well-established fact that a reduction in fertility status happens with increasing age. In women, we recognize that a decline in oocyte production occurs in their late 30s to early 40s. Men, on the contrary, can continue to father children well beyond their 40s, and to date there is no significant limit with respect to spermatogenesis. As paternal age continues to increase, many investigators have explored the effect of age on seminal parameters with the central question: Is advanced paternal age associated with diminished semen quality and a higher risk of infertility?

In a mouse model, studies have demonstrated that aging is correlated with histologic changes in testes and a decline in semen quality. Tanemura et al. (1993) demonstrated that older mice (at the age of 18 months) have several age-related changes, including an increased number of vacuoles in germ cells and a thinner seminiferous epithelium. By the age of 30 months, extremely thin seminiferous epithelia with very few spermatocytes or spermatids were found. In another study, Wang et al. (1993) found that total sperm production was significantly reduced in 22- and 30-month-old rats. Further studies also documented an increased incidence of preimplantation losses, mutation frequencies, and anueploidy in the offspring of older male mice (Serre et al., 1998; Walter et al., 1998; Lowe et al., 1995).

With the abundant evidence on the association between aging and male infertility in mice, the appropriate question is whether such a correlation exists in men. A comprehensive review by Kidd et al. (2001) evaluated the effects of male aging on semen quality in men; they looked at all studies in published literature between January 1 1980 and December 31 1999, and examined the outcome parameters of semen volume, sperm concentration, sperm motility, sperm morphology, pregnancy rate, and time to pregnancy/subfecundity (Kidd et al., 2001).

The overall consensus in the stated literature demonstrated a decrease in semen volume with increasing age. There have been 16 major studies examining semen volume with respect to advanced age. Though individual studies have varied with respect to the setting in which they were conducted (i.e., infertility clinics versus sperm banks), Kidd's meta-analysis of the results provides a comprehensive overview of the effect of male age on seminal parameters. Out of the 16 studies analyzed, 11 reported decreases in semen quality with increasing age. Two of these studies adjusted for the confounder of duration of abstinence and found that a statistically significant correlation still exists between decreasing semen volume and increasing age; they reported decreases of 0.15 to 0.5% for each increase in year of age (Fisch et al., 1996; Andolz et al., 1999). The duration of abstinence has been correlated with semen volume in a time-dependent fashion (Mortimer et al., 1982). Out of four studies showing no association between age and semen volume, only one study adjusted for duration of abstinence, and this study had a maximum patient age of 50 years (Schwartz et al., 1983). One study reported a slight increase (0.01mL/year) in semen volume with increasing age; however, this effect disappeared when adjusted for year of birth. Therefore, there is abundant evidence linking decreased semen volume with increased age, which becomes more significant in men over 50 years of age. When comparing men under the age of 30 with men aged 50 or older, most of the studies document decreases of 20 to 30% in semen volume between the two groups (Kidd et al., 2001). The correlation between advanced paternal age and semen volume suggests that age contributes to a decline in semen quality necessary for fertilization.

Unlike semen volume, the relationship between increasing age and sperm concentration was found to be inconclusive. Kidd et al. (2001) reviewed 21 studies examining the association between age and decreased sperm concentration and found no clear relationship between these parameters. Five studies documented decreasing sperm concentration with increasing age. However, only one study controlled for abstinence and year of birth as potential confounders; this study found a decrease in sperm concentration of 3.3% per year of age and also a 66% decrease in concentration from age 30 to 50 (Auger et al., 1995). Six studies found little or no association between age and sperm concentration, and none of these studies adjusted for duration of abstinence. Eight studies documented that with increasing age, sperm concentration had linear increases from 0.03 to 3.3% per year of age. Only two of these studies adjusted for duration of abstinence as a confounder and, interestingly enough, the increase in sperm concentration per year of age was found to be minimal (Fisch et al., 1996; Andolz et al., 1999). Based on the review by Kidd et al. there is substantial inconsistency among the studies exploring the relationship between sperm concentration and age. Even the results of the studies adjusting for duration of infertility are conflicting, suggesting that there is no clear association between sperm concentration and increasing paternal age.

Sperm motility, on the other hand, was found to be strongly linked to age as a substantial decline in sperm motility went hand-in-hand with increasing age. Kidd et al. (2001) reviewed 19 studies examining the relationship between the percentage of motile sperm and age; the majority of these studies (17/19) used visual assessment of sperm motility by light microscopy. Thirteen of the 19 studies found a decrease in sperm motility with increasing age; five of these studies adjusted for duration of abstinence, and the observed changes were statistically significant (Fisch et al., 1996; Rolf et al., 1996; Schwartz et al., 1983; Auger et al., 1995; Henkel et al., 1999). When these studies compared men age 50 or older to men under the age of 30, they reported a 3 to 37% decline in motility. Four studies reviewed by Kidd et al. found no association between age and sperm motility, and two studies reported a positive correlation; none of these studies adjusted for duration of infertility. Thus, the extensive body of evidence suggests that an inverse correlation exists between age and sperm motil-ity: there is a decline in sperm motility with increasing male age.

Likewise, an adverse correlation exists between sperm morphology and age. Kidd et al. (2001) reviewed 14 studies examining the relationship between age and sperm morphology. There were nine studies documenting a decrease in the percent of normal sperm with increasing age, five of which were found to be statistically significant. Controlling for the potential confounders of duration of abstinence and year of birth, Auger et al. (1995) reported that the percent of normal sperm decreased by 0.9% per year of age, and Andolz et al. (1999) reported a decline of 0.2% per year of age. When studies utilized age as a categorical variable, there was an observable trend with increasing age group and decreasing percent normal sperm. Five studies found no association between percent normal sperm and age, and none of these studies were found to be statistically significant. Despite the variation among morphological criteria to assess sperm abnormalities, there was a substantial amount of evidence linking increasing age to decreasing percent normal sperm.

The associations between increasing age and decreasing semen volume, sperm motility, and sperm morphology suggest that semen quality diminishes in the aging male. Whether age is analyzed as a continuous or categorical variable, the body of evidence suggests that a trend exists between increasing male age and decreasing semen quality based on these parameters. Aging in the human male results in degenerative changes to the prostate, such as a decrease in protein and water content (Schneider, 1978); these may contribute to the decrease in seminal volume and sperm motility. Additionally, age-related degenerative changes to the germinal epithelium can impact sperm morphology (Johnson, 1986). Though we recognize that advanced paternal age affects semen quality, it is necessary to study the impact of increasing age on fertility itself.

In his extensive analysis, Kidd et al. (2001) also studied the impact of increasing age on pregnancy rate, defined as the percent of male subjects whose partners achieved a pregnancy over a period of time, and subfecundity, defined as the percent of couples remaining infertile at a defined time point. Kidd et al. (2001) reviewed nine studies that examined the association between male age and pregnancy rate. The study population consisted of participants from infertility and assisted conception clinics. Seven of these studies reported a correlation between decreasing pregnancy rates and increasing age, and five of them reached statistical significance. However, four of the seven studies did not adjust for female age in the analysis, and female age is a well-established independent predictor of achieving pregnancy. Two of the studies that controlled for female partner age found that, after stratifying the study population into men under 30 and men over 50, the pregnancy rate in the cohort of older men was 23 to 38% lower (Rolf et al., 1996; Mathieu et al., 1995). One study did not find an effect of male age on pregnancy rates when female age was less than 35 years (Dondero et al., 1985), and another study reported lower pregnancy rates for couples where the man was over 30 years compared to those where the man was under 30 (van der Westerlaken et al., 1998); neither study determined the statistical significance of these differences. Overall, we see that there is an extensive amount of evidence linking increased paternal age and decreased pregnancy rate, with more substantial declines in men over the age of 50.

Kidd et al. (2001) also reviewed 11 studies evaluating the association between male age and subfecundity. Nine of these studies found that the time to pregnancy increases with male age, and four of the nine studies employed a proportional hazard analysis, which adjusted for varying lengths of observation before pregnancy was achieved. Seven of the nine studies reporting a direct correlation between paternal age and time to pregnancy reached statistical significance. In these studies, the increased risks of subfecundity with older age groups ranged from 11 to 250%. Only one study by Mathieu et al. (1995) adjusted for duration of infertility and irregular ovulation; Mathieu et al. found that after stratifying men into cohorts of age 35 or greater and less than age 30, there was a 60% decrease in the chance of initiating a pregnancy for the older men. Since this study was conducted for couples undergoing intrauterine artificial insemination, female age was found to be a poor prognostic value in predicting risk of pregnancy. There were two studies that did not show an association between male age and time to pregnancy; neither of these studies showed statistically significant differences (Kidd et al., 2001). Thus, the weight of the evidence suggests a strong correlation between paternal age and time required for a couple to achieve pregnancy.

A landmark study by Ford et al. (2000) explored the effect of paternal age on the likelihood of delayed conception. With a study population of 8515 planned pregnancies, the study found that older men were significantly less likely to impregnate their partners in less than six or less than 12 months, compared to their younger counterparts. After adjusting for various confounding factors such as age of the female partner, BMI, smoking, passive smoke exposure, education, duration of cohabitation, duration of oral contraceptive use, and paternal alcohol consumption, paternal age still remained highly significantly associated with conception within six or 12 months. If paternal age was treated as a continuous variable, there was a statistically significant linear relationship; the odds ratio for conception within six months decreased by 2% per year of age, and for conception within 12 months decreased by 3% per year of age. After comparing their study with the existent literature, Ford et al. concluded that the probability that a fertile couple will take greater than 12 months to conceive nearly doubles from approximately 8% when a man is less than 25 years old to approximately 15% when he is greater than age 35.

Kidd's review and Ford's study include a vast body of articles with variable evaluations and diverse patient populations. Additionally, the studies also vary in their adjustment of potential confounders as well as age-group stratifications. For these reasons, there can be no single conclusion about the linearity of the relationship between male age and semen parameters and/or fertility. Nevertheless, advanced paternal age is associated with a decline in semen quality and fertility status. As paternal age continues to increase in industrialist societies, it is worthwhile to continue engaging in a dialogue about the risks of infertility associated with a population of aging potential fathers.

Testosterone Decline

As with women, the levels of sex hormones in men decline with age (Harman et al., 2001). The drop is not as steep or as sudden as that associated with menopause, but it can be equally significant for fertility and overall well-being. Recently, there has been a lot of interest in declining testosterone levels in men. The roughly 1% per year decline in testosterone levels after age 30 has been termed andropause and is associated with a plethora of congenital and acquired disease-syndromes (McLachlan, 2000).

Previous longitudinal studies have demonstrated that abnormally low testosterone levels are present in elderly men (Sparrow et al., 1980; Harman et al., 2001; Feldman et al., 2002). Several large-scale studies in healthy, fertile men have evaluated mean values for serum testosterone (Ferrini et al., 1998). Additionally, there have been numerous cross-sectional investigations documenting lower concentrations of total testosterone and/or free testosterone in older men (Vermeulen et al., 1972; Gray et al., 1991). Most recently, the Massachusetts Male Aging Study, a large population-based random-sample cohort, reported that in a cohort of 1,709 healthy men aged 40 to 70 with a mean age of 55.2 years, the mean total testosterone value was 520 ng/mL. In follow-up data approximately a decade later, another cohort of 1,156 healthy men with a mean age of 62.7 years had a mean total testosterone value of 450 ng/mL (Feldman et al., 2002). This is a decline in testosterone in the same population of men sampled approximately 10 years later. Feldman et al. quantified the decreasing testosterone levels as a cross-sectional decline of 0.8%/ year of age and a longitudinal decline of 1.6%/year within the follow-up data. Other aging studies also have reported a longitudinal decline in serum testosterone (Rodriguez-Rigau et al., 1978; Morley et al., 1997). Additionally, Feldman et al. reported that the rate of decline was the same in apparently healthy men as well as men reporting a chronic illness, obesity, alcoholism, prescription medication, or prostate problems.

The decline in testosterone with age puts a greater number of elderly men at risk for developing hypo-gonadism. Rhoden and Morgentaler estimated that between two and four million men in the United States alone suffer from hypogonadism (defined as serum total testosterone levels lower than 325 ng per deciliter) (Rhoden et al., 2004). More alarmingly though, the same study reported that only 5% of these men are getting treatment for their symptoms, which include decreased libido and erectile dysfunction, loss of muscle mass and strength, weight gain, and declining cognitive function. Hypogonadism is also associated with type II diabetes, musculoskeletal frailty, cardiovascular disease, and the metabolic syndrome.

Because of the increasing prevalence of abnormally low levels of testosterone in elderly men, it is worthwhile to assess the relationship between hypogonadism and aging. The Baltimore Longitudinal Study on Aging, a large-scale study measuring total and free testosterone levels in 890 healthy men without any reported fertility or varicocele complications, found that using total testosterone, the frequency of detection of hypogonadal testosterone levels increased to about 20% of men over 60, 30% over 70, and 50% over 80 years of age (Harman et al., 2001). The study also found that 78% of men identified as hypogonadal by a single testosterone determination had low total testosterone levels on all subsequent samples. Additionally, a multivariate analysis confirmed that age is an independent predictor of a longitudinal decline in both total and free testosterone. Testosterone also decreased with increasing body mass index (BMI), independent of age.

To rectify the increased prevalence of hypogonadism in the aging male, treatments such as exogenous testosterone replacement and stimulation of endogenous testosterone production are gaining tremendous popularity. Sales of prescription testosterone products have soared more than 500% since 1993 and continue to increase (Bhasin et al., 2001). This enormous increase is not without risks; indiscriminate use of testosterone supplements can raise the risk of prostate problems, blood disorders, and infertility.

It has been established that there is a natural decline in serum testosterone as a process of aging; however, it demands to be explored if there are subsets of men with lower serum testosterone levels at an earlier age. Varicoceles are a well-established condition causing infertility. Varicoceles affect sperm function, and several studies suggest that they may contribute to testicular dysfunction and induce a subhypogonadal or hypo-gonadal state. Animal experiments have demonstrated an association between varicoceles and decreased serum testosterone biosynthesis (Rodriguez-Rigau et al., 1978). However, such studies in humans have not shown as strong an association. Gorelick and Goldstein reported that infertile males with varicoceles have a mean serum testosterone level that is within the limits of normal (Gorelick et al., 2000). Yet, Younes (2000) reported that mean serum testosterone was substantially decreased in male infertility patients with varicoceles compared to controls. Though there have been several further studies examining the testosterone profile of infertile men with varicoceles, results continue to be conflicting (Nagao et al., 1986; Comhaire et al., 1975).

At Columbia University Medical Center, we retrospectively reviewed testosterone levels of 237 men presenting with male factor infertility and clinical varico-celes between 1994 and 2004 who underwent varico-celectomy. For the entire cohort of men, the median age was 36.0 years, and the average testosterone level was 389.7 ng/mL. Out of our sample, 30.3% (72/237) patients were found to be hypogonadal (testosterone < 300 ng/ mL). When stratified into groups, the student's t test of independent samples showed that infertile men with varicoceles under the age of 30 had a mean testosterone level of 420.3ng/mL and those age 50 or older had mean testosterone level of 342.1 ng/mL (p = 0.05); men between the ages of 30 and 49 had a mean testosterone level of 389.2 ng/mL (Shah et al., 2005). This is the largest study to date reporting the testosterone profile of infertile men with varicoceles. Infertile men with varicoceles have a much lower serum testosterone level than was previously anticipated, with almost one-third being hypogona-dal. With increasing age, we found a trend indicating that older men have even lower testosterone levels than younger men. A similar study by Su et al. (1995) confirmed this trend and demonstrated that correction of the varicocele can improve testosterone levels for infertile men with varicoceles.

The lower testosterone levels observed in older men compared to younger men in our study population may implicate progressive local damage of the varicocele on testicular function. Previous studies suggest that various mechanisms may account for the testicular dysfunction associated with varicoceles (Howards, 1995). Both intra-scrotal and intratesticular temperatures are higher in men with varicoceles compared to controls (Zorgniotti et al., 1979). However, not all investigators have found an association between higher intratesticular temperatures and varicoceles (Tessler et al., 1966). As a result, nonthermal mechanisms have been suggested to account for the effect of a varicocele on testicular function; reflux of renal and adrenal metabolites from the renal vein, decreased blood flow, and hypoxia have all been postulated, and there is substantial evidence that smoking augments varicocele-induced testicular dysfunction (Comhaire et al., 1974; Saypol et al., 1981; Chakraborty et al., 1985; Klaiber et al., 1987). It is now accepted that infertility in the varicocele patient may be multifactorial, and the associated testicular dysfunction appears to worsen with age. Our data suggests this as well. Chehval and Purcell reported that varicoceles have a progressive effect on semen quality, which has also been reported by other studies (Chehval et al., 1992). Though there is abundant evidence that varicoceles are associated with lower semen quality over time, there is limited data available discussing the progressive effect that clinical varicoceles have on testosterone status. For this reason, further studies need to explore this trend as it may lead to hypogonadism in a substantial population of men. Additionally, it is worthwhile to investigate whether repair of the varicocele can improve testosterone levels in these hypogonadal men.

Advanced Paternal Age and Reproductive Capacity

Population studies within the United States reveal a significant increase in paternal age, with many couples postponing childbearing until their mid-30s to mid-40s. According to the CDC birth statistics, the average maternal age in 2003 was 25.1, which represents an increase from the average maternal age of 21.4 years in 1974. A trend toward advanced parental age is simultaneously occurring in American men. The birth rate among men 25 to 44 years has been steadily increasing since the 1970s, whereas the birth rate of men less than 25 years has been decreasing (Hamilton et al., 2003). An improved understanding of the effects of increased parental age on the developing fetus and newborn is imperative for counseling older couples preparing for childbearing. Advanced paternal age has been suggested to result in increased spontaneous abortions, autosomal dominant disorders, trisomy 21, and recently, schizophrenia.

Women aged 35 years or greater are at higher risk than younger women for adverse reproductive events including infertility, abortion, congenital abnormalities, and perinatal mortality. Paternal age often correlates with maternal age and can confound the effects of advanced maternal age. The first connection between spontaneous abortion and paternal age was raised during an analysis of fetal death certificates in 1939 (Yershalmy, 1939). Recent data confirms the association between advanced paternal age and the risk of spontaneous abortion. A prospective study of 5,121 American women revealed that the risk of spontaneous abortion increased with advanced paternal age (Slama et al., 2005). A prospective analysis of 23,821 women from the Danish National Birth Cohort further demonstrated that pregnancies fathered by men 50 years or older had almost twice the risk of spontaneous abortion when compared with pregnancies with younger fathers after adjustment for maternal age, reproductive history, and maternal lifestyle during pregnancy (Nybo Andersen et al., 2004). Although the correlation between advanced paternal age and spontaneous abortion is well demonstrated, there remains debate within the current literature regarding which trimester is at greatest risk with advanced paternal age. De La Rochebrochard and colleagues (2002) utilized the unique single variable ''couple age'' to elucidate the interaction between maternal and paternal age and the risk of spontaneous abortion. The retrospective data collected from this multicenter European study revealed that the effects of advanced paternal age and maternal age are cumulative; the risk of spontaneous abortion is highest if both partners are advanced in age. It is theorized that this increased risk of spontaneous abortions associated with advanced maternal or paternal age reflects chromosomal abnormalities in the developing fetus.

In this regard, advanced parental age is a recognized risk factor for many genetic abnormalities in the developing newborn. In men, advancing age decreases semen volume, percent normal sperm, and sperm motility (Rolf et al., 1996). Though these factors adversely affect fertility, the genetic integrity of the sperm is also at risk. In contrast to oogenesis, spermatozoa are continuously produced and undergo lifelong replication, meiosis, and spermatogenesis (Evans, 1996). This continued replication allows for spontaneous mutations within the paternal cell line. Apoptosis of sperm with damaged DNA is an essential aspect of spermatogenesis that ensures selection of normal sperm DNA (Roosen-Runge, 1973). As men age, the rate of genetic abnormalities that occur during spermatogenesis increases. Investigation of advanced paternal age in the murine model reveals age-dependent effects on the meiotic and premeitotic phase of sperm development. These abnormalities in replication result in both aneuploidy and structural abnormalities in male germ cells (Lowe et al., 1995). Additionally, the frequency of these numerical and structural aberrations in sperm chromosomes increases with increasing paternal age in humans (Sartorelli et al., 2001). This age-related increase in sperm cells with highly damaged DNA results from both increased double-strand DNA breaks and decreased apoptosis during spermatogenesis (Singh et al., 2003).

As a result, advanced paternal age is associated with many autosomal dominant disorders such as Apert syndrome, achondroplasia, osteogenesis imperfecta, progeria, Marfan syndrome, Waardenburg's syndrome, and thanatophoric dysplasia (Lian et al., 1986). Apert syndrome results from an autosomal dominant mutation on chromosome 10, mutating the fibroblast growth factor receptor 2 (FGFR2). The incidence of sporadic Apert syndrome increases exponentially with paternal age, resulting in part from an increased frequency of FGFR2 mutations in the sperm of older men (Glaser et al., 2003). Achondroplasia results from an autosomal dominant mutation on FGFR-3. Data from clinical achondroplasia registries reveal that 50% of affected children were born to men 35 years or older. In addition, the rate of achondroplasia increased exponentially with increasing paternal age (Orioli et al., 2004). The Muenke-type craniosynostosis results from an autosomal dominant mutation in FGFR-3 resulting entirely from the paternal allele. The average paternal age of children with Muenke-type craniosynostosis has been reported as 34.7 years (Rannan-Eliya et al., 2004). Therefore, men as young as 35 years are at higher risk for many autosomal dominant disorders, most notably costochondrodysplasias.

In addition to structural errors and resultant autosomal dominant disorders, aneuploidy errors in germ cell lines also occur at higher rates with advanced parental age. Trisomy 21 or Down syndrome is a common aneuploidy error that affects 1/800 to 1000 newborns (Cunningham et al., 2001). The association of advanced maternal age and trisomy 21 was first documented as early as 1933 (Fisch et al., 2001). Further amniocentesis data from the European collaborative study of Ferguson-Smith and Yates determined that the rate of trisomy 21 increases exponentially from a maternal age of 35 years (Ferguson-Smith et al., 1984). Although the correlation between trisomy 21 and advanced maternal age is well documented, it is only recently that the affects of advanced paternal age have been elucidated. Investigation of the meiotic nondisjunctional error in trisomy 21 reveals the origin of the extra chromosome 21 to be paternal in 5 to 20% of cases (Antonarakis, 1991; Jyothy et al., 2001). Despite this recognized paternal origin, to our knowledge no chromosomal studies evaluating parental origin of chromosomal defects in offspring and paternal age are available.

Early studies from the 1970s and 1980s failed to demonstrate a consistent effect related to advanced paternal age. Initial epidemiological studies utilizing city and state birth registries failed to show any correlation between trisomy 21 and advanced paternal age while confirming the effect of advanced maternal age (Erickson, 1978; Hook, 1987). In contrast, an evaluation of the Medical Birth Registry of Norway from 1967 to 1978 that included 685,000 total births and 693 cases of Down syndrome revealed an increased risk of Down syndrome with a paternal age of 50 years or greater (Erickson et al., 1981). As parental age is increasing in the United States, recent studies provide more men of advanced age to evaluate. The New York State Department of Health congenital malformations registry containing 3,419 trisomy 21 births was analyzed from 1983 to 1997 and demonstrated a 111% and 60% increase in women and men over 35 years, respectively. This contemporary evaluation revealed no effect of parental age on trisomy 21 until 35 years. A paternal age effect was apparent in association with a maternal age of 35 years or greater and was most pronounced when maternal age was 40 years or greater. The rate of Down syndrome with a combined parental age greater than 40 years was 60/10,000 births that represents a six-fold increase compared with parents less than 35 years (Fisch et al., 2003). Advanced paternal age in interaction with advanced maternal age significantly increases the risk of trisomy 21 and may possibly explain the exponential increase in trisomy 21 in women greater than 35 years.

In contrast to the effects of combined parental age in trisomy 21, schizophrenia is associated with spontaneous mutations arising in the paternal germ cells. Although schizophrenia is a complex disease of unclear etiology, there is substantial evidence for a genetic component (Kendler et al., 1993). Since most individuals with schizophrenia are born to unaffected parents and have reduced reproductive activity, it is unclear how the disease is maintained within the population (Fananas et al., 1991). Early studies from the 1960s and 1970s suggested an association between advanced paternal age and the development of schizophrenia (Hare et al., 1979; Gregory, 1959). Recent studies have confirmed this association between advanced paternal age and schizophrenia in large population-based studies (Zammit et al., 2003). A 12-year evaluation of the Jerusalem birth registry and the Israel psychiatric registry that included 658 individuals with schizophrenia revealed that the risk of schizophrenia increased monotonically with increasing paternal age. This increased risk culminated in a relative risk of 2.96 (95% confidence interval, 1.60-5.47) for offspring of men 50 years or greater (Malaspina et al., 2001). Conversely, maternal age demonstrated no effect on the development of schizophrenia. A Swedish birth registry study revealed that the association between paternal age and schizophrenia was present in families without previous history of the disorder, but not in those with a family history. Based upon the stronger association between paternal age and schizophrenia in people without a family history, the authors suggested that accumulation of de novo mutations in paternal sperm contributed to the risk of schizophrenia (Sipos et al., 2004).

Men of advanced paternal age, much like their female counterparts, are at greater risk for spontaneous abortion and genetic abnormalities. The continually replicating spermatogonia and the decreasing apoptotic rate are likely causes of the amplified meiotic and premeiotic errors in the male germ cell line. These chromosomal abnormalities increase in the aging male and potentially result in spontaneous abortion, autosomal dominant disorders, trisomy 21, and schizophrenia. In light of the trend toward delayed childbirth, the potential deleterious effects of advanced parental age become increasingly important. Therefore, appropriate prenatal counseling of older couples regarding the effects of advanced parental age on the developing fetus and newborn is imperative.

Conclusion

This brief discussion of the aging male demonstrates an unappreciated reality: men have biological clocks that affect their fertility, hormones levels, and the genetic quality of their sperm. This clock plays a role on a personal level (when couples must grapple with infertility or birth defects) and on a public health level (when society must decide policies governing, for instance, insurance coverage for advanced fertility treatments such as in vitro fertilization). Women should no longer be viewed as solely responsible for age-related fertility and genetic problems. Infertility is not just a woman's problem, and with the new awareness of a new male biological clock, couples and their physicians can much more accurately proceed with proper testing, diagnosis, and (if needed) treatment of the male. The field of male-factor infertility is still very young and much more research is needed to fully characterize risks and to find more effective treatments. We also need to better understand the cellular and biochemical mechanisms of ''gonadal'' aging in order to find safe, effective ways to delay this process and, in effect, ''rewind'' the male biological clock. Doing so will lessen the potential for adverse genetic consequences in offspring, improve the sexual and reproductive health of aging males, and increase a woman's chance of having healthy children by correcting defects in the male reproductive machinery (Fisch, 2005).

Recommended Resources

Harry Fisch, M.D.

Professor of Clinical Urology

Male Reproductive Center of Columbia University/

New York Presbyterian Hospital

944 Park Avenue, New York, NY 10028

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