The male biological clock

The male biological clock
Friday, October 21, 2011
After 41 your chances of becoming a father ‘decline rapidly’, warn researchers

LONDON: It is not just women that have to worry about their biological clock. Male fertility declines with age – with even a year making a difference, researchers have warned. They say that after the age of 41, a man’s odds of fathering a child decline rapidly.

And after 45, those who haven’t started a family and want one should start doing something about it.

But with the likes of Des O’Connor having his fifth child at 72, and Rod Stewart becoming father for the eighth time at the age of 66, other experts said the finding should be taken with a pinch of salt.

The warning comes from a study of IVF patients in which the man’s sperm fertilised an egg from a donor.

In the context of the study, the use of donor eggs allowed the researchers to separate out the effect of the man’s age from that of the woman’s. The donor eggs all came from young, healthy women and so any differences in pregnancy rate must be due to the sperm.

And the difference was clear, with fertility declining by up to seven per cent with each extra year on a man’s age between 41 and 45. After that, it declined even more rapidly.

The average age of the men whose partners got treatment through IVF was 41.

In the context of the study, the use of donor eggs allowed the researchers to separate out the effect of the man’s age from that of the woman’s.

The donor eggs all came from young, healthy women and so any differences in pregnancy rate must be due to the sperm. And the difference was clear, with fertility declining by up to seven per cent with each extra year on a man’s age between 41 and 45. After that, it declined even more rapidly.
The average age of the men whose partners got treatment through IVF was 41.

But the average age of those in which the IVF was unsuccessful was 45, the American Society for Reproductive Medicine’s annual conference heard.

The chances of pregnancy fell from 60 per cent at the age of 41 to just 35 per cent for the 45-year-olds.

Researcher Paula Fettback, of the Huntington Medicina Reproductiva clinic in Brazil, said: “Age counts.

“Men have a biological clock too. It is not the same as for women but they can’ t wait forever to have children.

“They have to think about having children, especially after 45.”

A second study presented at the conference backed up the warning.

There, fertility plummeted in male mice from a year old – equivalent to middle-age in people.

Fewer eggs were fertilised and fewer embryos grew long enough to be used in IVF.

Pregnancies took longer to occur and when they did, the miscarriage rate rocketed from zero using sperm from young animals, to over 60 per cent.

The researchers, from the Colorado Center for Reproductive Medicine, said they believed there would be ‘some parallel’ with men.

“We found an abrupt reproductive deterioration in mid-life, equivalent to humans in their 40s.”

Other studies have found that children of older fathers also run an increased risk of heart defects, autism, schizophrenia and epilepsy, and are almost twice as likely to die before adulthood.

.Male fertility showed a 21-23% annual decrease starting at the age of 39.

Gynecol Obstet Invest. 2011;71(4):229-35. Epub 2010 Dec 15.
Decline in human fertility rates with male age: a consequence of a decrease in male fecundity with aging?
Matorras R, Matorras F, Expósito A, Martinez L, Crisol L.
SourceHuman Reproduction Unit, Department of Obstetrics and Gynecology, Hospital de Cruces, Basque Country University, Baracaldo, Spain. roberto.matorras @ osakidetza.net

Abstract
BACKGROUND: The objective of this study is to investigate the influence of male age on human fertility, defined as the birth rate for a given population.

METHODS: Data from the Spanish National Statistics Institute (INE) for the year 2004 from a total of 454,753 newborn infants and sorted by male and female age groups were evaluated. In order to correct the influence of female age-related fertility, a different analysis was performed considering only women under 30 years of age.

RESULTS: From a demographic point of view, male fertility started to decline at 35-39 years of age. This decline is constant and follows an exponential pattern (slope -0.11 to -0.12). The trend persisted when the data were adjusted for every 1,000 men in the age group, as well as when only women under the age of 30 were considered. Male fertility showed a 21-23% annual decrease starting at the age of 39.

CONCLUSION: An exponential decrease in human fertility which is independent of the woman's age was observed with male aging. This decay is probably due to a downfall in male fecundity, closely related to a decline in sperm quality. However, social or behavioral causes for this trend cannot be excluded.

Copyright © 2010 S. Karger AG, Basel.

Advanced paternal and grandpaternal age and schizophrenia: A three-generation perspective.

Schizophr Res. 2011 Oct 13. [Epub ahead of print]
Advanced paternal and grandpaternal age and schizophrenia: A three-generation perspective.
Frans EM, McGrath JJ, Sandin S, Lichtenstein P, Reichenberg A, Långström N, Hultman CM.
SourceDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Abstract
BACKGROUND: Advanced paternal age has been linked with an increased risk of schizophrenia in the offspring. If age-related de novo mutations in the male germ line underlie this association, grandpaternal and paternal age would both be expected to influence the risk of schizophrenia. The aim of the current study was to explore the links between both paternal and grandpaternal age with respect to the risk of schizophrenia in a large, national register-based cohort.

METHOD: We linked the Swedish Multi-Generation and Hospital Discharge Registers and compared parents' ages at offspring birth for 20,582 schizophrenia-affected and 100,176 non-affected individuals. Grandparents' ages at the birth of the parent were compared between 2511 affected and 15,619 non-affected individuals. The risk of schizophrenia was examined with logistic regression when the predictor variable (parent or grandparent age) varied across age strata.

RESULTS: After adjusting for maternal age, birth year and proband sex, we confirmed that offspring of older fathers had an increased risk of schizophrenia. Compared to those with paternal age 20-24years, those with fathers >55years had a two-fold increased risk of schizophrenia. With respect to grandparent age, older maternal (but not paternal) grandfather age was associated with an increased risk of schizophrenia. Compared to maternal grandfather age 20-24years, those with maternal grandfathers >55years had a significantly increased risk of schizophrenia (adjusted odds ratio and 95% confidence intervals; 2.79, 1.71-4.56). The pattern of results was essentially unchanged when we examined male and female probands separately.

CONCLUSION: This is the first study to report an association between grandpaternal age and risk of schizophrenia. The selective effect of advanced maternal grandfather age suggests that the biological mechanisms involving the X-chromosome may differentially contribute to the association between paternal age and offspring risk of schizophrenia.

Copyright © 2011. Published by Elsevier B.V.

De novo copy number variants associated with intellectual disability have a paternal origin and age bias.

J Med Genet. 2011 Oct 3. [Epub ahead of print]
De novo copy number variants associated with intellectual disability have a paternal origin and age bias.
Hehir-Kwa JY, Rodríguez-Santiago B, Vissers LE, de Leeuw N, Pfundt R, Buitelaar JK, Pérez-Jurado LA, Veltman JA.
Source1Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Abstract
BackgroundDe novo mutations and structural rearrangements are a common cause of intellectual disability (ID) and other disorders with reduced or null reproductive fitness. Insight into the genomic and environmental factors predisposing to the generation of these de novo events is therefore of significant clinical importance.MethodsThis study used information from single nucleotide polymorphism microarrays to determine the parent-of-origin of 118 rare de novo copy number variations (CNVs) detected in a cohort of 3443 patients with ID.ResultsThe large majority of these CNVs (76%, p=1.14×10(-8)) originated on the paternal allele. This paternal bias was independent of CNV length and CNV type. Interestingly, the paternal bias was less pronounced for CNVs flanked by segmental duplications (64%), suggesting that molecular mechanisms involved in the formation of rare de novo CNVs may be dependent on the parent-of-origin. In addition, a significantly increased paternal age was only observed for those CNVs which were not flanked by segmental duplications (p=0.02).ConclusionThis indicates that rare de novo CNVs are increasingly being generated with advanced paternal age by replication based mechanisms during spermatogenesis.