Older men are having children, but the reality of a male biological clock makes this trend worriesome

Older men are having children, but the reality of a male biological clock makes this trend worrisome

Feature Article
Publish date: Jan 15, 2009By: Harry Fisch, MDSource: Geriatrics

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.
ABSTRACT
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 )
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.
Conclusions
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.
References
1. Fisch H, Hyun G, Golden R, et al. The influence of paternal age on Down syndrome. J Urol. 2003:169(6):2275-2278.
2. Eskenazi B, Wyrobek AJ, Sloter E, et al. The association of age and semen quality in healthy men. Hum Reprod. 2003;18(2):447-454.
3. Lewis BH, Legato M, Fisch H. Medical implications of the male biological clock. JAMA. 2006;296(19):2369-2371.
4. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. 2002;87(2):589-598.
5. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 2004;350(5):482-492.
6. Travison TG, Araujo AB, O'Donnell AB, et al. A population-level decline in serum testosterone levels in American men. J Clin Endocrinol Metab. 2007;92(1):196-202.
7. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001;86(2):724-731.
8. Imamoto T, Suzuki H, Yano M, et al. The role of testosterone in the pathogenesis of prostate cancer. Int J Urol. 2008;15(6):472-480.
9. Ford WC, North K, Taylor H, et al. Increasing paternal age is associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men. Hum Reprod. 2000;15(8):1703-1708.
10. Mathieu C, Ecochard R, Bied V. Cumulative conception rate following intrauterine artificial insemination with husband's spermatozoa: influence of husband's age. Hum Reprod. 1995;10(5):1090-1097.
11. Reichenberg A, Gross R, Weiser M, et al. Advancing Paternal Age and Autism. Arch Gen Psychiatry. 2006;63(9):1026-1032.
12. Malaspina D, Harlap S, Fennig S, et al. Advancing Paternal Age and the Risk of Schizophrenia. Arch Gen Psychiatry. 2001;58(4):361-367.
13. de la Rochebrochard E, Thonneau P. Paternal age and maternal age are risk factors for miscarriage: results of a multicentre European study. Hum Reprod. 2002;17(6):1649-1656.
14. Walter CA, Intano GW, McCarrey JR, et al. Mutation frequency declines during spermatogenesis in young mice but increases in old mice. Proc Natl Acad Sci. 1998;95(17):10015-10019.
15. Andolz P, Bielsa MA, Vila J. Evolution of semen quality in North-eastern Spain: a study in 22,759 infertile men over a 36 year period. Hum Reprod. 1999;14(3):731-735.
16. Auger J, Kunstmann JM, Czyglik F, et al. Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med. 1995;332(5):281-285.
17. Cocuzza M, Athayde KS, Agarwal A, et al. Age-related increase of reactive oxygen species in neat semen in healthy fertile men. Urology. 2008;71(3):490-494.
18. Manoharan M, Ayyathurai R, Nieder AM, Soloway MS. Hemospermia following transrectal ultrasound-guided prostate biopsy: a prospective study. Prostate Cancer Prostatic Dis. 2007;10(3):283-287.

Harry Fisch- His advice? "If my son or daughter was to ask, I'd tell them to have kids early -- and that's before 30."

Yo, dude, check your bio clock -- now
New studies warn that it isn't just women who become less fertile as they age
Sarah Treleaven , The Ottawa Citizen
Recently, I've had a lot of conversations about baby-making with my male friends.

"I worry that I might be too selfish to ever have children," said my friend Joe, 29, somewhat pensively over gin and cucumber cocktails. Ditto for Colin, who just broke up with a woman he loves because she wants to have kids in the next few years and, at 35, he just doesn't feel ready yet. Kids or no, they both feel like they have all the time in the world to decide.

I, on the other hand, just turned 30 and have been making a lot of jokes about needing an apartment with a second bedroom for my soon-to-be-frozen eggs.



Email to a friend

Printer friendly
Font:****Lots of women wring their hands about having a baby. Not only do we have to worry about our plummeting fertility (which begins to tank in our mid-20s), but we also have to worry about job retention and advancement once those kids (come biology, adoption or surrogacy) eventually appear. And it's the physical limitations of the female ability to procreate that have placed such a heavy emphasis on the reproductive biological clock, shaping the way many women live, work and even date.

But evidence is increasingly emerging that men, too, have a reproductive biological clock -- and that it ticks much more loudly than most of us have thought. Even as stories occasionally emerge about septuagenarian and octogenarian men becoming proud papas -- author Saul Bellow, for example, fathered a child at 84 -- several recent studies are challenging the conventional wisdom that men have an invincible ability to procreate.

A French study released in July found that women's pregnancy rates drop and miscarriages increase when the mother is over 35 and the father is over 40. Another study suggests that a man's fertility begins to decrease as early as his 20s. Researchers from the University of California at Berkeley and the Lawrence Livermore National Laboratory tested men between the ages of 22 and 80, and found that semen volume and sperm motility were both significantly compromised by aging.

Additionally, the increased odds for older fathers producing genetic abnormalities have been well documented, and studies have demonstrated that fathers over 40 are six times more likely to produce an autistic child than fathers under 30.

The numbers related to schizophrenia are similarly compelling. A study utilizing health databases in Jerusalem found that fathers over 40 were twice as likely to produce schizophrenic children as fathers who were under 25; for fathers over 50, the odds tripled when compared to fathers who were under 25.

Dr. Harry Fisch, director of the Male Reproductive Center at New York-Presbyterian Hospital/Columbia University Medical Center and the author of The Male Biological Clock, says that he's been ringing the alarm bell for years.

"There's a female biological clock; we all agree on the decline in fertility, more genetic problems and a decline in estrogen.

"The same thing happens in men -- a little bit differently, but essentially the same," Fisch says. "Why is it important? Well, demographically more men and women are waiting until they're over 30 to have a baby."
1 2 3 next page

The offspring and offspring of the offspring suffer from the Ticking of the Male Biological Clock

Harry Fisch said as far as the connection between older paternal age and devastating genetic disorders, where you look you find it! The main predictor for non-familial autism is PATERNAL AGE.

Dolores Malaspina has studied paternal age and genetic neurocognitive disorders extensively and does not state this lightly:

Though more research is needed, Malaspina says it’s possible that — just like women — the prime time for becoming a dad is one's 20s and early 30s.
“Men," she says, "your biological clocks are ticking, too.”

If you want healthy children and grandchildren plan to have children earlier in life rather than after your very early 30s.

Sperm donors are limited to men under 35 or under 30 in cryobanks that know about the gene DNA deterioration in older men.

Read on if you want to know more about the Male Biological Clock Advancing Paternal Age and Genetic Disorders

It is very possible that Paternal Age is the Major Predictor for autism---Harry Fisch, MD

Harry Fisch is the author of The Male Biological Clock, The Patient's Guide to Vasectomy Reversal, The Patient's Guide to Varicocele Repair and Managing The Vasectomy Patient. He is one of the nation's leaders in the diagnosis and treatment of male infertility and microsurgical vasectomy reversal. Dr. Fisch is director of the Male Reproductive Center and directs urologic microsurgery in the Department of Urology at Columbia University Medical Center of New York Presbyterian Hospital in New York City. He is also professor of clinical urology at Columbia University, where he was recently named Teacher of the Year in his department.
For over fifteen years, Dr. Fisch has focused his research, practice, and surgery on male infertility and reproduction.




From the Psychology Today article:


"Everybody was familiar with the concept of women's biological clock, but when we introduced 'male' to the equation, the reaction was 'What are you talking about? Men can have children at any age,'" recalls urologist Harry Fisch, director of the Male Reproductive Center at Columbia Presbyterian Hospital in New York City and author of The Male Biological Clock. "It became a social issue. Men do not like to be told they have a problem."
Nonetheless, a virtual tidal wave of recent research has made it irrefutable: Not only does male fertility decrease decade by decade, especially after age 35, but aging sperm can be a significant and sometimes the only cause of severe health and developmental problems in offspring, including autism, schizophrenia, and cancer. The older the father, the higher the risk. But what's truly noteworthy is not that infertility increases with age—to some degree, we've known that all along—but rather that older men who can still conceive may have such damaged sperm that they put their offspring at risk for many types of disorders and disabilities.
"Men thought they were getting off scot free, and they weren't. The birth defects caused by male aging are significant conditions that can cause a burden to families and society," says Ethylin Wang Jabs, professor of pediatric genetics at Johns Hopkins University and leader of a recent study showing the link between aging paternity and certain facial deformities in offspring. "We now know that men and women alike could be increasing the risk of infertility or birth defects by waiting too long to have children." In other words, by looking for perfection in your life before you conceive, there's a very real chance you'll have less perfect kids."
In the past several years, studies worldwide have found that with each passing decade of their lives and with each insult they inflict on their bodies, men's fertility decreases, while genetic risk to offspring slowly mounts. The range of findings is staggering: Several studies have shown that the older the man, the more fragmented the DNA in his ejaculated sperm, resulting in greater risk for infertility, miscarriage or birth defects. Investigations out of Israel, Europe, and the United States have shown that non-verbal (performance) intelligence may decline exclusively due to greater paternal age; that up to a third of all cases of schizophrenia are linked to increasing paternal age; and that men 40 and older are nearly six times more likely to have offspring with autism than men under age 30. Other research shows that the risk of breast and prostate cancer in offspring increases with paternal age. "



------------------------


This is why autism and 100s of other disorders are rapidly rising:


By Rick Brewer
Record Staff Writer
October 23, 2007 6:00 AM
Jerry Syrovatka says that at 51 he can still run circles around his 8-year-old daughter and 4-year-old son.

But who knows how long that will last?

The Weston Ranch resident is part of a growing phenomenon among baby boomers: men who father children well past the age of 40.

Excellent Article on the Male Biological Clock, Mark Teich, Harry Fisch, etc.

Mark Teich tells it like it is!

"A Man's Shelf Life"
small excerpt, the whole article is a must read!

"In the past several years, studies worldwide have found that with each passing decade of their lives and with each insult they inflict on their bodies, men's fertility decreases, while genetic risk to offspring slowly mounts. The range of findings is staggering: Several studies have shown that the older the man, the more fragmented the DNA in his ejaculated sperm, resulting in greater risk for infertility, miscarriage or birth defects. Investigations out of Israel, Europe, and the United States have shown that non-verbal (performance) intelligence may decline exclusively due to greater paternal age; that up to a third of all cases of schizophrenia are linked to increasing paternal age; and that men 40 and older are nearly six times more likely to have offspring with autism than men under age 30. Other research shows that the risk of breast and prostate cancer in offspring increases with paternal age. ".......



"The autism findings are even more disturbing: Men 40 and older in the Israeli study were almost six times as likely to have offspring with autism than men under 30. Some researchers believe that older fathers may hold a clue to the vast upsurge in autism cases in the past decade. "With older and older couples having children—in the past two years, for the first time, more babies are being born to women over age 30 than under age 30, and on average, male partners tend to be older than female partners—it's very feasible that paternal age is a major predictor of autism," asserts Fisch.".....



The spin is that the mother's age is relevant is autism. BUT :

“The exact contrary of what is generally believed is often the truth. ”
- Jean de la Bruyère

Harry Fisch, Nancy Snyderman, The Tip of the Iceberg

http://allday.msnbc.msn.com/archive/2007/03/13/88225.aspx
caught up with Dr. Nancy after her segment on the male biological clock this morning. I asked her what the one take-away point should be from the segment, and she said quite simply: "There is one." That is, there IS a male biological clock, and it's something that everyone should take into account when family planning and deciding to have children. The female biological clock often receives the attention because it's a clear and simple fact -- women cannot have children after a certain age. However, men can still reproduce at any age, and that's the reason that the male risk factors often drop off the radar screen.

Some of the statistics are quite alarming, however. Of the nearly 6 million fertility problems in the US each year, roughly 40% of them are attributed to the man. Of all the babies born with Down Syndrome to women over the age of 35, HALF of them are actually sperm-related. (Source for both statistics: Dr. Harry Fisch, director of the Male Reproductive Center at New York-Presbyterian Hospital/Columbia University Medical Center.)
WATCH VIDEO.