A Most Important Peer Reviewed Paper on the Reality of the Male Biological Clock
January 15, 2009
Older men are having children, but the reality of a male biological clock makes this trend worrisome
By Harry Fisch, MD
Dr Fisch is Professor of Clinical Urology, Department of Urology, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York City.
Disclosure: The author states that he has no financial relationship with any manufacturers in this area of medicine.
Couples are waiting longer to have children, and advances in reproductive technology are allowing older men and women to consider having children. The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome. The age-related changes associated with the male biological clock affect sperm quality, fertility, hormone levels, libido, erectile function, and a host of non-reproductive physiological issues. This article focuses on the potentially adverse effects of the male biological clock on fertility in older men. Advanced paternal age increases the risk for spontaneous abortion as well as genetic abnormalities in offspring due to multiple factors, including DNA damage from abnormal apoptosis and reactive oxygen species. Increased paternal age is also associated with a decrease in semen volume, percentage of normal sperm, and sperm motility. Older men considering parenthood should have a thorough history and physical examination focused on their sexual and reproductive capacity. Such examination should entail disclosure of any sexual dysfunction and the use of medications, drugs, or lifestyle factors that might impair fertility or sexual response. Older men should also be counseled regarding the effects of paternal age on spermatogenesis and pregnancy.
Fisch H. The aging male and his biological clock. Geriatrics. 2009;64(1):14-17.
Keywords: apoptosis, hypogonadism, male biological clock, male infertility, paternal age, spermatogenesis, testosterone
The phrase "biological clock" commonly refers to the declining fertility, increasing risk for fetal birth defects, and altered hormone levels experienced by women as they age. Abundant scientific evidence suggests that men also have a biological clock.1,2 The hormonal and physiological effects of the male clock are linked with testosterone and fertility declines, as well as pregnancy loss and an increased risk of birth defects.3 In this article, we review the effects of the male biological clock, and the association between advanced paternal age and decreased spermatogenesis, pregnancy rates, and birth outcomes.
Male testosterone levels (both total and free) decline roughly 1% per year after age 30.4 The rate of decline in one study4 was not significantly different between healthy men and those with chronic illnesses or multiple comorbidities. This decline can shift men whose testosterone levels are in the low end of the normal spectrum to levels considered below-normal, or hypogonadal (testosterone <325 ng/mL) as they age. An estimated 2 to 4 million men in the United States fall in this category, either from age-related declines, illness, injury, or congenital conditions.5 The population of hypogonadal men is increasing due both to the aging of the general population and unknown factors that appear to be suppressing the average levels of testosterone in more recent birth cohorts.6 The increasing prevalence of abnormally low testosterone levels in elderly men was demonstrated in the Baltimore Longitudinal Study on Aging, which determined that hypogonadal testosterone levels were present in approximately 20% of men over 60, 30% over 70, and 50% over 80 years of age.7
Sub-normal testosterone levels are associated not only with decrements in fertility and sexual response, but also a wide range of other health problems such as declines in muscle mass/strength, energy levels, and cognitive function, as well as increased incidence of weight gain (particularly central adiposity), type 2 diabetes, the metabolic syndrome, and cardiovascular disease. Testosterone replacement therapy to address the wide range of health problems related to hypogonadism is becoming increasingly popular. Delivery via gels or transdermal patches can result in physiologically normal levels of testosterone, which is preferable to the spiky levels obtained via testosterone injections. Oral formulations are under development but none have progressed beyond the clinical trial phase. Fears that testosterone replacement therapy may promote the growth of prostate carcinomas has abated in light of findings from several studies that find no such link.8
Declining fertility and increasing birth defects
It has long been recognized that female fertility declines with age and, obviously, ceases with menopause. Only relatively recently, however, has it been proven that male fertility also declines with age—often significantly so—and that semen quality and the related risk for birth defects is also sensitive to aging. Studies demonstrate that men older than age 35 are twice as likely to be infertile (defined as the inability to initiate a pregnancy within 12 months) as men younger than 25 years.9 Among couples undergoing fertility treatments with intra-uterine insemination, the amount of time necessary to achieve a pregnancy rises significantly with the age of the male. Further, after controlling for maternal age, couples in which the male is older than 35 have a 50% lower pregnancy rate compared with couples in which men are 30 or younger.10
The risk of birth defects is also now known to be related to paternal age. A significant association has been found between advancing paternal age and the risk of autism spectrum disorder (ASD) in children.11 Offspring of men 40 years or older were 5.75 times more likely to have ASD compared with offspring of men younger than 30 years, after controlling for year of birth, socioeconomic status, and maternal age.
Another study finds a link between paternal age and a higher risk of fathering a child with schizophrenia.12 Men older than 40 were more than twice as likely to have a child with schizophrenia as men in their 20s. A similar influence of paternal age on the risk of having a child with Down syndrome has been reported by several research teams,1 with paternal age a factor in half the cases of Down syndrome when maternal age exceeded 35 years. Other investigators have found that the rate of miscarriages increases with rising paternal age when maternal age was older than 35.13 Thus, there is convincing evidence for an effect of paternal age alone, as well as a combined effect of advancing paternal and maternal age, on increased risks of genetic abnormalities leading to miscarriage or disease in their children. A retrospective multi-center European study revealed that the effects of advanced paternal age and maternal age are cumulative. If both partners are advanced in age, the risk of spontaneous abortion is higher.
Mechanisms behind biological clock effects
The precise genetic and physiological malfunctions underlying the observed links between advanced paternal age and congenital abnormalities remain uncertain although clues have been discovered in recent years. Studies in the murine model, for example, have shown that changes in testicular architecture affect semen quality. At 18 months (defined as "older" in a mouse), several age-related changes occur, including increased number of vacuoles in germ cells and thinning of the seminiferous epithelium. At the age of 30 months, seminiferous epithelia with scant spermatocytes were identified. Overall, total sperm production was significantly reduced and mutation frequency was significantly increased in "older" mice.14
Such changes in testicular architecture, as well as changes in the germinal epithelium, prostatic epithelium, and a host of genetic alterations, undoubtedly underlie the well-documented declines in human semen parameters observed over the years. The literature (11 of 16 published studies) clearly shows, for example, a decrease in semen volume with advanced age. In 2 studies, which adjusted for the confounder of abstinence duration, a decrease in semen volume of 0.15-0.5% was reported for each increase in year of age.15 The semen volume of men aged 50 or older was decreased by 20-30% when compared with men younger than age 30. An association between advanced paternal age and decreased sperm motility is also apparent. In a review of 19 studies, 13 found a decrease in sperm motility with increasing age. Five studies adjusted for the duration of abstinence—a key potential confounder—and found statistically significant declines. A comparison of men age 50 or older to men younger than 30, revealed a 3% to 37% decline in motility.
Abnormal sperm morphology is also tied to advanced paternal age. In 14 studies reviewed, 9 studies found decreases in the percentage of normal sperm with advancing age with the rates of decline ranging from 0.2% per year to 0.9% per year of age when controlling for confounders of duration of abstinence and year of birth.16
The male biological clock also "ticks" at the level of genes. The genetic integrity of sperm has been shown in several studies to decline with age. For example, age is associated with declines in the number of Leydig and Sertoli cells, as well as with an increase in arrested division of germ cells. There also seems to be an increasing failure of the body's ability to "weed out" genetically inferior sperm cells via the mechanism of apoptosis. Spermatozoa are continuously produced and undergo lifelong replication, meiosis, and spermatogenesis. An essential aspect of spermatogenesis that ensures selection of normal DNA is the process of apoptosis of sperm with damaged DNA. Since the rate of genetic abnormalities (such as double-strand breaks) during spermatogenesis increases as men age, the rate of apoptosis should rise as well. This, however, does not seem to be the case, for reasons that remain unknown, which results in higher levels of genetically damaged sperm in older men.
Oxidative stress may also play a role in the observed rise in the frequency of numerical and structural aberrations in sperm chromosomes with increasing paternal age. Spermatozoa have low concentrations of antioxidant scavenging enzymes, which makes them particularly susceptible to DNA damage from reactive oxygen species. A recent study found that seminal reactive oxygen species levels are significantly elevated in men older than 40 years of age.17
Aneuploidy errors in germ cell lines also occur at higher rates with advancing paternal age. The aneuploidy error of trisomy 21, for example, is responsible for Down syndrome. The rate of many autosomal dominant disorders such as Apert syndrome, achrondroplasia, osteogenesis imperfecta, progeria, Marfan syndrome, Waardenburg syndrome, and thanatophoric dysplasia increases with advanced paternal age. Apert syndrome, for example, is the result of an autosomal dominant mutation on chromosome 10, mutating fibroblast growth factor receptor 2 (FGFR2). With increasing paternal age, the incidence of sporadic Apert syndrome increases exponentially, resulting in part from an increased frequency of FGFR2 mutations in the sperm of older men.
The role of medications and comorbidities
The effects of the male biological clock can be exacerbated by both medications and comorbidities. Pharmacologically mediated fertility declines and/or sexual dysfunction has been demonstrated for antihypertensive drugs, antidepressants, and hormonal agents. Seminal emission can be blocked by alpha blocker medications, which are used to treat many symptoms of the lower urinary tract. Gonadotropin-releasing hormone agonists, which are used for prostate cancer treatment, can directly affect sperm production and testosterone levels. High doses of anabolic steroids, sometimes used for enhancement of performance and muscle enlargement, cause reduction of sperm production, which may be permanent. Erectile dysfunction, ejaculatory disorders, and decreased libido can be caused by the 5-alpha reductase inhibitors.
Sexual function and reproductive function can substantially decline in males treated for prostate cancer. Treatments such as radiotherapy, surgery or hormones, alone or in combination, can result in these dysfunctions in treated men of any age, though the severity of effects increases with age. A report found that ultrasound-guided needle biopsy of the prostate was associated with some abnormal semen parameters.18 Since prostate biopsy is more common in men 50 or older, this can be an issue for older would-be fathers.
The fact that men and women are waiting longer to have children, and that advances in reproductive technology are allowing older men and women to consider having children, carries a generally unrecognized public health risk in the form of increased infertility and risk for birth defects and other reproductive problems. CDC birth statistics show the average maternal age rose from 21.4 years of age in 1974 to 25.1 years of age in 2003. Paternal age is rising as well.
The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome. This article has demonstrated a host of potential reproductive problems among older men. Semen parameters as well as semen genetic integrity decline with age, which leads to an increased risk for spontaneous abortion as well as genetic abnormalities in offspring. The decreasing apoptotic rate and increase in reactive oxygen species among the rapidly replicating spermatogonia are possible mechanisms behind an amplification of errors in germ cell lines of older men. Such errors may account for the observed increases in Down syndrome, schizophrenia, and autosomal dominant disorders in children born to older fathers.
Future research may elucidate in greater detail the etiology and manifestation of the male biological clock in older men. Novel methods to reverse or slow the clock may be discovered by improved understanding of the cellular and biochemical mechanisms of gonadal aging. This research may diminish potential adverse genetic consequences in offspring and increase the chances that older couples will have a healthy child.
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