01-09 Effect of aging on the male reproductive system

Lesson 09 of 15

Effect of aging on the male reproductive system

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Saturnino Luján Marco, MD Andrology Unit IVI Valencia Department of Surgery. University of Valencia

Index

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BackgroundPotential consequences of advanced paternal age Anatomical changes Genetics and paternal age Impact of paternal age on the mental health of offspring Management of reproductive risks in advanced paternal age Conclusions

Background

Demographic changes

Background

Social/technological changes

Background

Tendency to become parents at an older age

Births to parents > 40 years old 4.1% - 8.9% Births to parents > 50 years old 0.5% - 0.9%

Advanced paternal age

Poorer outcomes

Tendency to become parents at an older age

Potential consequences of advanced paternal age

Decreased pregnancy rate

Increase in perinatal complications

Increase in malignant tumors in offspring

Mental health risks

Potential consequences of advanced paternal age

Testicular function alteration

• Anatomical changes
• Hormonal changes
• Spermiogram alteration

Genetic alteration

• Sperm DNA integrity (fragmentation)
• Telomere length
• De novo mutations
• Chromosome structure
• Epigenetic factors

Potential consequences of advanced paternal age

Testicular function

The fountains of youth

Anatomical changes

Anatomical changes

Anatomical changes

Epithelial thinning

Decreased tubule diameter

Thickening

Hormonal changes

Spermiogenesis. Acrosome phase

Hypothalamus

GnRH

Hypophysis

FSH

LH

Testicles

Leydig cells

Germ cells/Sertoli cells

Estradiol

Testosterone

Inhibin B Activin

HYPOTHALAMIC-HYPOPHYSEAL-TESTICULAR AXIS

FSH/LH

Hormonal changes. Andropause

Hormonal changes

Why does testosterone drop?

• Leydig cell number reduction
• Decreases 50% 20-48 years old vs 50-76 years old
• Role of andropause
• Total and free testosterone reduction

Hormonal changes

Spermiogram changes

Spermiogram changes

Spermiogram changes

At what age does the decline start?

• >34 years total number
• >40 years concentration (mil /mL)
• >40 years morphology
• >43 years mobility
• >45 years volume

Genetics and paternal age

Genetic

Genetics and paternal age

DNA fragmentation

Genetics and paternal age

DNA fragmentation

Genetics and paternal age

DNA fragmentation

• 40,668 men
• 19 items
• 17/19 articles demonstrate age impact with DFI
• DFI dx tool in >40 years

Genetics and paternal age

DNA fragmentation

• Lower probability of fertilization
• Longer time until fertilization
• DNA f better predictor than spermiogram
• Worse ICSI/IUI results

Genetics and paternal age

DNA fragmentation

Genetics and paternal age

DNA fragmentation

Good 0-30% Intermediate 31-70% High 71-100%

Telomere length

Telomere length

Telomere length. Leukocytes

• Greater Leu telomere length = less arteriosclerosis
• Greater survival
• Greater leukocyte telomere length = more breast Ca
• Lower survival

Telomere length and sperm

• Greater telomere length spz age
• Resistance to aging? Perpetuate species?
• Short telomeres spz = genomic instability
• Impaired spermatogenesis

DNA mutations

DNA mutations

• Variants or de novo mutations
• Asymmetric premeiotic spermatogonia divisions
• Greater oxidative stress
• Postmeiotic chromatic remodeling errors

DNA mutations

• FGFR3 achondroplasia
• NRE5-1 sexual differentiation
• USP9Y gene (azoospermia)

Chromosomal aneuploidies

• Aneuploidy = abnormal number of chromosomes
• Meiosis failure
• Embryo aneuploidy = pregnancy failure
• 1% obtain LB
• 10% aneuploid spermatozoa but increases age

VER IMAGEN

Chromosomal aneuploidies

Epigenetics

Nutrition Age Drugs/toxins Phenotypic variation

Epigenetics

Genetic silencing

Epigenetics

• Gene silencing
• Increase in methylated forms of cytosine (5-mc and 5-hmc)
• 1.76% per year
• Angelman syndrome
• Beckwith-Wiedemann syndrome

Epigenetics

Epigenetics

Impact of paternal age on offspring

Decreased pregnancy rate in ART

Comparison diagram LB parent >40y vs <40y

Decreased pregnancy rate in ART

Comparison diagram pregnancy rate parent >40y vs <40y

Decreased pregnancy rate in ART

Miscarriages parent >40y vs <40y

Perinatal outcomes

13.2% of premature births and 14.5% of low-weight babies born become parents before 45 years of age

Perinatal outcomes

Congenital defects

Paternal age and risk of hematological malignancies

• 63% greater hematological cancer >35y vs >25y
• Lymphoblastic leukemia 13% for every 5 years of increase in paternal age

Paternal age and risk of hematological malignancies

Impact of paternal age on the mental health of offspring

Management of reproductive risks in advanced paternal age

¿Cuándo se considera edad paternal avanzada?

> 40 años “lo suficientemente joven” 40 años

Current status of the management of reproductive risks associated with advanced paternal age

"A growing number of older men entering or re-entering fatherhood"

Management of reproductive risks in advanced paternal age

• Accept and know the risks
• Gamete donation?
• Counseling
• Study the man
• Varicocele?
• Seminal obstruction
• Genetic disorders
• Endocrine disorders

Management of reproductive risks in advanced paternal age

• Planned egg freezing
• Sperm freezing
• Chromatin damage
• Economic costs
• ART need
• Need for studies
• Sperm selection

Conclusions

• Trend towards older paternal age
• Worse perinatal outcomes and offspring health
• Genetic and functional alterations
• Advanced paternal age > 40 years?
• Individualized approach
• No age discrimination

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• Yip BH, et al. Parental Age and Risk of Childhood Cancers: A Population-Based Cohort Study From Sweden. Int J Epidemiol (2006) 35 (6):1495–503.
• Choi JY, et al. Association of Paternal Age at Birth and the Risk of Breast Cancer in Offspring: A Case Control Study. BMC Cancer (2005) 5:143.
• Xue F, et al. Parental Age at Delivery and Incidence of Breast Cancer: A Prospective Cohort Study. Breast Cancer Res Treat (2007) 1043:331–40.