It’s Not Just A Woman’s Age – A Word On Older Fathers
A Word On Older Fathers, Part 1 of 2
When couples present for infertility treatment, we tend to focus primarily on the age of the egg [advanced maternal age (AMA)] as this is the primary prognostic factor for a successful outcome. But what about the sperm? What are the risks of advanced paternal age (APA) and should we be spending more time counseling couples on these risks?
The difference between the sexes regarding age-related impact on fertility and adverse reproductive outcomes are due to the very different way the gametes (egg and sperm) are produced. Both eggs and sperm are derived from stem cells called germ cells. These precursor cells that give rise to the final egg and sperm first undergo a number of replicating cell divisions (mitosis) before they switch gears and enter the terminal process of meiosis. When a stem cell begins meiosis – it is a biological dead-end in that this given cell can never again replicate. A female egg stem cell that enters meiosis is destined to become one egg, while a male sperm stem cell is destined to become four sperm, but they can never again replicate themselves. The issue with the female is that prior to birth, after undergoing only 20-30 mitotic cell divisions1, ALL of her stem cells will switch to meiosis and thus after birth, they can never again replicate themselves. This is why a woman is born with a finite supply of eggs; the eggs she is born with must last her entire reproductive life. In the female, meiosis of germ cells is spread over many years as her germ cells begin meiotic cell division as a fetus, but never complete it. The eggs remain frozen in the middle of meiosis until they are ovulated years later. This prolonged wait results in an increase in abnormalities in chromosome separation leading to a high rate of abnormal chromosome numbers (aneuploidy) in the mature egg.
With the male, on the other hand, the germ cells will continue to replicate throughout a man’s lifetime. Meiosis in the male is completed as a continues process without the starts and stops seen in the female. So as a man ages, the germ cells that give rise to his sperm will have undergone an ever increasing number of mitotic cell divisions before being diverted to the production of sperm through meiosis. The germ cells of a 40-year old man will have undergone approximately 600 mitotic cell division, while that of a 60-year old man will have undergone over 1000 mitotic cell divisions. While this ensures a lifetime supply of fresh sperm, every cell division represents a chance to introduce an error in the DNA that would eventually effect the sperm. As a male ages, therefore, the ongoing mitotic cell division of his germ cells results in an increasing risk of genetically abnormal sperm. In addition, many of these abnormal germ cells will never progress to form mature sperm; This is thought to play a role in the well know age related decline in sperm parameters.
How old is old and what genetic abnormalities are seen will be discussed in part 2.
- Crow, J. F. The origins, patterns and implications of human spontaneous mutation. Nat.Rev.Genet 1(1), 40-47. 2000.
- Johnson, S. L., Dunleavy, J., Gemmell, N. J., and Nakagawa, S. Consistent age-dependent declines in human semen quality: a systematic review and meta-analysis. Ageing Res.Rev. 19C, 22-33. 11-21-2014
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