Until fairly recently, it had been assumed that paternal age had only a minor impact on reproductive outcome. Several recent provocative studies have raised the specter of a causal association between paternal age and significant medical conditions in the offspring. However, the observational nature of these studies leaves open the possibility that factors other than age itself may be responsible for observed results. This article reviews the available data on this topic, with an eye toward providing a basis for clinical counseling of the older man who wishes to have a child.
In women there is a well-established link between advanced age and (1) reduced fertility and (2) increased risk of birth defects. The effect of age on male fertility and pregnancy outcomes has been less well studied. Until fairly recently, it had been assumed that paternal age had only a minor impact on reproductive outcome. This view has been reinforced by the routine occurrence of older men becoming fathers and the occasional news report of documented paternity in men more than 80 years old. Unlike women, there is clearly no universal or abrupt age-related decline in fertility in men.
Recent publications, however, have suggested that aging men do indeed demonstrate a decline in fertility, and several provocative studies have raised the specter of a causal association between paternal age and significant medical conditions in the offspring. This article reviews the available data on this topic, with an eye toward providing a basis for clinical counseling of the older man who wishes to have a child.
Changing patterns in the age of parenting in the United States
In the mid-1960s, the National Survey of Family Growth (NSFG) initiated the collection and analysis of data from families and relationships across socioeconomic and racial lines. The strengths of this survey lie in its breadth and volume of participants and the length of time over which it has been conducted. The most recent analysis of NSFG data from 2002 has shown a trend toward later parenting.
Since the 1970s, the average age at first marriage for women has increased by almost 5 years, accompanied by an increase in mean maternal age at first birth from 21.4 to 25.1 years. Additionally, the percentage of first-time mothers aged 30 years or older has increased dramatically, from 3.9% to 25.1%. There are multiple factors contributing to these changes including an increasing number of women completing their education, entering the workforce, and establishing careers before choosing to have children .
Mean paternal age is more difficult to establish because the age of the father usually is not listed on birth certificates. It is important to note that 31% of first-time fathers are aged 30 years and older . It generally is recognized that fathers’ ages have increased also. By age 40 to 44 years, 22% of men have not had a child, 20% have had one child, 25% have had two children, and 33% have had three or more.
The effects of advancing paternal age on fertility and pregnancy outcomes
Advancing maternal age has been shown to have a great impact on fertility and on the rate of birth defects and genetic abnormalities of the offspring. Fertility rates clearly decline by age 37 years and are greatly reduced by age 40 years. This decline seems to result from loss of oocytes and a decline in oocyte quality .
In contrast, no dramatic or sudden changes in male reproductive physiology mirror the changes seen in women as they approach the fifth decade of life, and thus the impact of advancing paternal age on fertility outcomes has been less certain. In clinical practice it is not unusual to see men in their fifties and even sixties who wish to achieve a pregnancy with younger female partners. These men and their partners often inquire whether paternal age should play a role in their decisions.
Concerns regarding the impact of paternal age on pregnancy and its outcomes has become even more appropriate as advances in reproductive treatments allow clinicians to assist the creation of pregnancies in an ever-widening pool of men with compromised fertility. Intrauterine insemination, in vitro fertilization, and intracytoplasmic sperm injection, for instance, have increased the reproductive options and potential for couples suffering from infertility caused by a significant male and/or female factor. For management of male-factor infertility, significant advances in techniques such as microsurgical testicular sperm acquisition, vasectomy reversal, and various forms of assisted reproductive technologies have enabled couples who previously had no opportunity to have children using these techniques. Increased investigations into the genetics of male-factor infertility, including Y-chromosome microdeletions, are ongoing .
The key questions related to male aging encountered during clinical practice are
- 1.
Does older male age decrease the likelihood of achieving a pregnancy?
- 2.
Does older male age increase the likelihood of genetic abnormalities or other adverse health outcomes in the offspring if a pregnancy occurs?
The effects of advancing paternal age on fertility and pregnancy outcomes
Advancing maternal age has been shown to have a great impact on fertility and on the rate of birth defects and genetic abnormalities of the offspring. Fertility rates clearly decline by age 37 years and are greatly reduced by age 40 years. This decline seems to result from loss of oocytes and a decline in oocyte quality .
In contrast, no dramatic or sudden changes in male reproductive physiology mirror the changes seen in women as they approach the fifth decade of life, and thus the impact of advancing paternal age on fertility outcomes has been less certain. In clinical practice it is not unusual to see men in their fifties and even sixties who wish to achieve a pregnancy with younger female partners. These men and their partners often inquire whether paternal age should play a role in their decisions.
Concerns regarding the impact of paternal age on pregnancy and its outcomes has become even more appropriate as advances in reproductive treatments allow clinicians to assist the creation of pregnancies in an ever-widening pool of men with compromised fertility. Intrauterine insemination, in vitro fertilization, and intracytoplasmic sperm injection, for instance, have increased the reproductive options and potential for couples suffering from infertility caused by a significant male and/or female factor. For management of male-factor infertility, significant advances in techniques such as microsurgical testicular sperm acquisition, vasectomy reversal, and various forms of assisted reproductive technologies have enabled couples who previously had no opportunity to have children using these techniques. Increased investigations into the genetics of male-factor infertility, including Y-chromosome microdeletions, are ongoing .
The key questions related to male aging encountered during clinical practice are
- 1.
Does older male age decrease the likelihood of achieving a pregnancy?
- 2.
Does older male age increase the likelihood of genetic abnormalities or other adverse health outcomes in the offspring if a pregnancy occurs?
Age and semen analysis
A number of studies have attempted to determine the impact of age on semen analysis parameters. In one retrospective study, semen analyses results of 66 men aged 50 years and older were compared with those of 134 men aged 21 to 25 years in patients referred to an andrology clinic over a 3-year period . Total sperm count and sperm concentration were unaffected by age. Progressive motility (27%), percentage of morphologically normal spermatozoa (44%), and semen volume (29%) were significantly lower in older men than in younger men. The greater percentage of morphologically abnormal sperm in older men resulted from flagellar abnormalities, such as coiled or bent tails, indicating possible epididymal dysfunction. In addition, serum testosterone levels were significantly lower in the group of older men than in younger men (3.0 ng/mL versus 3.6 ng/mL, a decline of 17%).
Levitas and colleagues performed a retrospective study to examine the relationship between age and semen parameters among 6022 men who had sperm concentrations of 20 million/mL or higher. A peak semen volume of 3.51 ± 1.76 mL was observed in men between the ages of 30 and 35 years old, and the lowest volume of 2.21 ± 1.23 mL was observed in men aged 55 years and older. Sperm motility was inversely related to age, with the greatest motility (44%) for men younger than 25 years and the lowest motility (24%) for men 55 years and older. A 54% reduction in total motile sperm was noted between men aged 30 to 35 years and men older than 55 years. Interestingly, sperm concentration increased with advancing age. The lowest mean sperm concentration of 62 × 10 6 /mL was observed among men younger than 25 years old, and the highest sperm concentration was noted among men 55 years and older. This latter group had sperm concentrations almost 20% higher than men 45 to 54 years old and almost 35% higher than men younger than 25 years.
Carlsen and colleagues performed a 4-year longitudinal study of 158 young men from Copenhagen in which each participant provided a semen sample for analysis at the outset and on an annual basis for the duration of the study. The median age of men entering the study was 19.1 years. Over the 4 years of the study, no statistically significant changes were noted in sperm concentration, total sperm count, or sperm morphology. Variation in methodology over the course of the study made it difficult to assess changes in motility.
Eskenazi and colleagues also reviewed the impact of age on semen parameters. In this cross-sectional study of 97 nonsmoking men aged 22 to 80 years without known fertility problems, semen volume was found to decrease by 0.03 mL for each year of advancing age, and motility decreased by 0.7% per year. No significant relationship between age and sperm concentration was noted when four azoospermic men were excluded from the analysis. Men in their twenties had median sperm concentrations and total sperm counts of 92 × 10 6 /mL and 345 × 10 6 , respectively, whereas men 50 to 59 years old had a median sperm concentration of 101 × 10 6 /mL and total sperm count of 251 × 10 6 . Morphology was not examined in the study. There was thus no evidence of an age “threshold” for any semen parameter nor more than a minor change in sperm values over time. It is worth noting that several of the older men studied had normal semen analysis results.
In a related study that assessed quantitative aspects of sperm motility using computer-assisted technology, aging was associated with diminished linear motion. This observation may indicate some reduction in fertility potential among older men despite normal-appearing motility results, but this concept remains to be demonstrated .
Taken together, these studies generally have demonstrated no more than a mild reduction in semen parameters with age. Specifically, sperm concentration seems largely unaffected, with some studies revealing limited and variable changes in motility and morphology. Although, a decrease in ejaculatory volume with age seems to be consistent, this change by itself is unlikely to affect overall fertility.
The effect of age on reproductive physiology
Changes in testicular histology with age
In general, the size of the testicles remains constant throughout a man’s adult life. Histologic studies, however, have shown that age is associated with a decline in the number of Leydig and Sertoli cells, a thickening of the basement membrane of the seminiferous tubules, and an increase in arrested divisions of germ cells. These spermatogenic cells are largely responsible for the majority of testicular mass, and their decline results in smaller testes in some men .
It has been suggested that these changes, in turn, may lead to decreased efficacy of spermatogenesis, with fewer mature sperm produced per tubule . These histologic changes exhibit a high degree of variability, however, and some men seem to preserve apparently normal spermatogenesis well into their nineties.
Endocrine changes affecting reproduction
A number of large studies, including the Massachusetts Male Aging Study, have shown a decline in serum testosterone levels in men with advancing age. On average, total testosterone levels decline by 1% to 2% per year. A decrease in bioavailable testosterone and free testosterone occurs with age as well. In contrast, sex hormone–binding globulin levels increase with age in men . This age-related decline in serum testosterone represents the combination of reduced central responsiveness to circulating androgen levels together with decreased steroidogenic capacity of Leydig cells .
The relative decline in testosterone production may affect fertility at the testicular level where relatively high androgen levels seem to be important to support spermatogenesis. In addition, changes in testosterone concentrations may influence the actions of seminal proteins, such as heparin-binding proteins, which seem to be involved in sperm motility .
Testosterone and estradiol are present in the seminal fluid and are involved in the growth and maintenance of the surface epithelium of the male reproductive tract The decline in androgenic stimulation associated with aging thus has the potential to impact male fertility at multiple levels. Because a wide range of serum testosterone concentrations can be seen with normal fertility, however, the impact of the gradual decline of testosterone on male fertility remains to be determined.
Changes in sexual function with aging
Aging may impair sexual function in men, which in turn may impact fertility. In the Massachusetts Male Aging Study, the prevalence of erectile dysfunction increased with advancing age so that more than 50% of men develop moderate or severe erectile dysfunction by the eighth decade. The increasing incidence of erectile dysfunction is multifactorial: the age-related decline in serum testosterone also may cause erectile dysfunction, as well as diminished libido and difficulty achieving ejaculation .
Pharmacologically mediated male infertility
A large body of clinical experience and published reports in the literature link many commonly prescribed drugs with sexual dysfunction. This dysfunction is more likely to occur in the aging man who may be taking multiple medications. A variety of antihypertensive drugs, antidepressants, and hormonal agents, to name a few, commonly have been associated with sexual dysfunction .
Medications may affect fertility by reducing libido, inhibiting ejaculation, causing retrograde ejaculation, contributing to erectile dysfunction, or by direct gonadotoxic effects . For example, the serotonin reuptake inhibitor class of antidepressants can reduce libido and cause delayed ejaculation or complete anorgasmia. The alpha-blocker medications used to treat lower urinary tract symptoms can reduce or block seminal emission.
Medications that directly affect sperm production include gonadotropin-releasing hormone agonists used in the treatment of prostate cancer. These agents produce castrate levels of testosterone, which in turn results in severe disruption of spermatogenesis. Paradoxically, exogenous testosterone administration for the treatment of hypogonadism results in similar impairment of spermatogenesis via negative feedback on the hypothalamus and pituitary. The suppressive effect on sperm production with physiologic replacement doses of testosterone generally is reversible. In contrast, the reduction in sperm production may be permanent among athletes and bodybuilders who have a history of anabolic steroid use for performance enhancement, because of the extremely high doses employed and the common practice of combining multiple agents. In addition, several chemotherapeutic agents, such as cyclophosphamide and other alkylating agents, have a direct and often permanent gonadotoxic effect on spermatogenesis.
The association of erectile dysfunction and aging has resulted in the widespread use by older men of the oral phosphodiesterase inhibitors, such as sildenafil, tadalafil, and vardenafil. Although there were initial concerns regarding a possible negative effect of these medications on male reproductive function or sperm values, the evidence available to date has been reassuring.
Analysis of sperm motility after exposure to sildenafil using computer-assisted semen analysis and acrosome-reaction testing by fluorescein staining was performed on 57 men . The sperm were incubated with sildenafil at 37°C for up to 180 minutes. It was found that the number and velocity of progressively motile sperm were significantly increased by sildenafil between 15 and 135 minutes. Sildenafil also caused a significant increase in the proportion of acrosome-reacted sperm. The clinical significance of these results remains to be determined.
In another study looking at the effects of tadalafil , spermatogenesis was examined in men taking placebo versus 10 or 20 mg tadalafil administered daily for 6 months to healthy men and to men who had mild erectile dysfunction. Chronic daily administration of tadalafil had no apparent adverse effects on semen volume or on sperm concentration, motility, or morphology.
Lower urinary tract symptoms and reproduction
Lower urinary tract symptoms and sexual dysfunction secondary to benign prostatic hyperplasia (BPH) are common, highly bothersome conditions in men, and the prevalence of both disorders increases with age .
Current medical treatment of BPH symptoms consists of monotherapy with alpha1-adrenoceptor antagonists, 5-alpha-reductase inhibitors, or a combination of these. The 5- alpha-reductase inhibitors may, rarely, cause erectile dysfunction, ejaculatory disorders, and diminished libido. The use of alpha-blockers is associated with failure of seminal emission or greatly reduced ejaculatory volume in a substantial percentage of men . Combined therapy places men at risk for the adverse sexual effects associated with either type of drug.
Finasteride has been used to treat BPH and male-pattern baldness. In men taking finasteride at 5 mg daily for symptoms of BPH, ejaculate volumes decrease by approximately 25%. One study looking at the semen parameters of men taking low doses of finasteride (1 mg) for hair loss found no changes in semen parameters, however .
Surgical therapies for BPH, such as transurethral resection of the prostate, are well known to result in retrograde ejaculation and, less often, in postoperative urethral strictures. These adverse events result in diminished or even complete absence of antegrade ejaculation.
Related posts:
Hormonal Evaluation of the Infertile Male: Has It Evolved?
Assessing Sperm Function
Anejaculation and Retrograde Ejaculation
Ejaculatory Duct Obstruction
Reassessing Reconstruction in the Management of Obstructive Azoospermia: Reconstruction or Sperm Acquisition?
Intrauterine Insemination and Male Subfertility
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