The Male Biological Clock

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The Male Biological Clock

• John L. Frattarelli, M.D., FACOG
• Reproductive Medicine Associates of New Jersey

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Male Menopause/Adrenopause?
As men age

• Decreased
• Testosterone levels
• Libido
• Hair
• Muscle mass
• Strength

• Increased
• Weight
• Erectile dysfunction
• Infertility
• Depression
• Cholesterol

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Male Infertility

• 30-40 infertile couples
• Etiologies
• stress, fever, infections, drugs,
  work/environment hazards, age
• Semen analysis
• spermatogenesis 74 days
• 14 days to pass through testis

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Male Infertility
Hum Reprod Update 1999 5(2) 120
AGE?
Percent ()
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Semen Analysis

• Volume gt2.0 cc
• pH 7.2 - 7.8
• Concentration 20 mil/mL
• Total gt40 mil
• Motility gt50 forward/25 rapid
• Morphology gt30 gt14
• WBC lt1 mil/mL

WHO, 1992 Kruger Strict Criteria, 1999
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Sperm Density
J Urol 1951 66(3) 436
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Sperm Morphology features as a Prognostic Factor
in IVF
Kruger TF et al. Fertil Steril 1986 46 1118
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Effect of male age on sperm quality and
fertilityKidd et al. Fertil Steril 2001

• Review of the published literature from 1980-1999
• Volume
• Decrease 3-30 from age 30 to 50
• Seminal vesicle and prostate changes
• Concentration
• No change
• No control for abstinence
• Motility
• Decrease 3-37 from age 30 to 50
• Prostate and epididymal changes
• Morphology
• Decrease 4-22 from age 30 to 50
• Germinal epithelium and epididymal changes
• Pregnancy rates
• Confounded by age but a trend for a 38 decrease
  from age 30 to 50

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Male Factor Treatment Pregnancy rate results
from RCT

• Bromocriptine
• 4 trials
• OR 0.7, 95 CI 0.15-3.24
• Androgen therapy
• 11 trials, n930
• OR 1.1, 95 CI 0.75-1.61
• Clomiphene citrate
• 10 trials, n738
• OR 1.56, 95 CI 0.99-2.19

Cochrane Reviews 2003
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IUI

• Need 1 million motile sperm
• Prefer gt 5 million motile
• Little benefit gt10 million motile

• IUI vs Timed Coitus
• Meta-analysis
• 17 RCT, n3662 cycles
• Natural cycle
• OR 2.43 (1.5-3.8)
• COH
• OR 2.14 (1.3-3.5)
• Common OR for fecundity 2.37
• 95 CI 1.43-3.90

Cochrane Reviews 2003
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Evidence for declining fertility in older men
Ford et al. Hum Reprod, 2000

• 8515 planned pregnancies
• Large population study questionnaire
• Gestations gt24 weeks

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Evidence for declining fertility in older men
Ford et al. Hum Reprod, 2000

• Adjusted odds ratios
• Adjusted for partner age, BMI, smoking, passive
  smoke, education, duration of cohabitation,
  duration of OC use, alcohol consumption

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Outcome rates and male age in 1023 donor oocyte
cycles.
Frattarelli in press, 2007
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Outcome rates and male age in 1023 donor oocyte
cycles.
Frattarelli in press, 2007
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Couple age and Miscarriage rate
de La Rochebrochard and Thonneau, Hum Reprod 2002

• N3174
• Data from European Multicenter Study on
  Infertilty and Subfertility 1991-1993
• Combined male and female ages to make a single
  categorical variable for multiple logistic
  regression

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Outcome rates and male age in 1023 donor oocyte
cycles.
Frattarelli in press, 2007
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The impact of paternal age on aneuploidy rates in
first trimester losses

• Controls IVF patients using autologous oocytes
  (n23)
• Mean female age 28.7 1.1
• Mean male age 33.7 7.6
• Donor oocyte group (n50)
• Mean donor age 27.8 3.9
• Mean female age 39.6 5.0
• Mean male age 41.5 6.8

Frattarelli in press, 2007
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Early hints at the link between paternal age and
birth defects

• 1912-Dr. Weinberg
• Achondroplasia more often in younger siblings
• Dr. Penrose
• Paternal age associated with de novo AD mutations
• Now gt20 disorders associated with paternal age
• Alpert, Crouzon, Pfeiffer, Marfan,
  Achrondoplasia, neurofibromatosis, osteogenesis
  imperfecta

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Meiosis vs Mitosis

• Women have 24 divisions in the cells that give
  rise to their eggs
• Men have gt30 rounds of mitosis prior to puberty
• About 23 replications per year

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Spermatogenesis

• 23 replications per year
• Age 30
• 380 mitotic divisions
• Age 40
• 610 mitotic divisions
• Age 50
• 840 mitotic divisions

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Male Infertility

• Infertile males with oligospermia or azoospermia
  (n 9766)
• 5.8 incidence of chromosomal abnormalities
• 4.2 sex chromosome
• 1.5 autosome
• Baseline fertile males 0.5

Johnson, Fertil Steril 1998
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Karyotypic Abnormalities

• Frequency is inversely proportional to sperm
  concentration
• Most common anomaly is Klinefelter syndrome
• atrophic hyalinized testes depleted of germ cells

Sharlip et al. Fertil Steril 2002
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Male Infertility

• Cytogenetic surveys of oligospermic and
  azoospermic males
• oligo- 4.6 with cytogenetic abnormalities
• 1.6 sex chromosomal
• 3.0 autosomal
• azoo- 13.7 with cytogenetic abnormalities
• 12.6 sex chromosomal
• 1.1 autosomal

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DNA damage in sperm

• N66
• Ages 20-57
• Gradual increased in DNA damage
• Most pronounced after age 35
• ?Apoptosis decreases with age?

Singh et al. Fertil Steril 2003
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Influence of Paternal Age on Down Syndrome

• Incidence from 1983-1997
• N 3419 cases
• NY state DOH congenital malformations registry
• No paternal influence until gt35 years
• Paternal age contributes 50 risk

Fisch et al. J Urol 2003
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Schizophrenia
Paternal Age Group RR (95 CI)
lt24 1
25-29 1.14 (0.8-1.5)
30-34 1.42 (1.0-2.0)
35-39 1.64 (1.1-2.4)
40-44 1.73 (1.1-2.7)
45-49 2.02 (1.2-3.5)
gt50 2.96 (1.6-5.5)
Maternal Age Group RR (95 CI)
lt24 1
25-29 1.01 (0.8-1.3)
30-34 1.10 (0.8-1.4)
35-39 1.2 (0.8-1.7)
gt40 1.2 (0.8-1.7)
Risk at paternal age of 40 1/110 Similar to the
female risk of Downs at the same age 2
incidence of schizophrenia for males gt50 years
-Israeli psychiatric registry -Controlled for age
of other parent -Also for sex, ethnicity, and
education
Malaspina et al. Arch Gen Psychiatry 2001
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Microdeletions

• Yq11 microdeletions
• 10-15 azo- / severely oligozoospermic men
• AZF azoospermia factor
• AZFa to AZFc in the Yq11.21-23 region
• To small to be detected by karyotyping
• Can be detected by PCR

Brandell et al. Hum Repro 1998
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Microdeletions

• N5000 infertile males screened for Y-chromosome
  mutations in the AZF region
• 8.2 infertile males
• 0.4 fertile males
• Foresta et al. Endo Rev 2001

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Intracytoplasmic Sperm Injection (ICSI)
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ICSI-Derived Offspring

• Of concern because of increased sperm aneuploidy
  in OAT males
• 1 incidence of sex chromosome aneuploidy in ICSI
  conceptions
• 0.14 - 0.19 baseline (non-ICSI)
• ? Unidentified Klinefelters mosaics

• Consider karyotyping all infertile males?
• Consider prenatal diagnosis for all ICSI-derived
  pregnancies?

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5 year follow up of ICSI Children

• Examination at 5 years of age
• Matched to spontaneous conception controls
• Maternal age
• Gender
• Child age
• Same centers
• Assessment
• Growth
• General health
• Chronic illnesses
• Surgical intervention
• Neurological development
• Results
• ICSI children had more surgical interventions
  (13 vs 10.5)
• Otherwise equivalent outcomes

Bonduelle et al Reprod Biomed Online 2004 91-101
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Summary

• Male aging
• Decreased spermatogenesis
• Decreased fertility
• Increased miscarriage risk
• Increased aneuploidy rates

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Recommendations

• Karyotyping should be strongly considered
• translocations, sex chromosome aneuploidy,
  gonadal mosaicism
• Screening for AZF microdeletions
• Preimplantation genetic screening
• Amniocentesis/CVS
• Genetic Counseling
• Donor sperm

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