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The Male Biological Clock

The Male Biological Clock. John L. Frattarelli, M.D., FACOG Reproductive Medicine Associates of New Jersey. Decreased Testosterone levels Libido Hair Muscle mass Strength. Increased Weight Erectile dysfunction Infertility Depression Cholesterol. Male Menopause/Adrenopause?.

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The Male Biological Clock

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  1. The Male Biological Clock John L. Frattarelli, M.D., FACOG Reproductive Medicine Associates of New Jersey

  2. Decreased Testosterone levels Libido Hair Muscle mass Strength Increased Weight Erectile dysfunction Infertility Depression Cholesterol Male Menopause/Adrenopause? As men age:

  3. 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

  4. Male Infertility Hum Reprod Update 1999; 5(2): 120 AGE? Percent (%)

  5. Semen Analysis • Volume >2.0 cc • pH 7.2 - 7.8 • Concentration 20 mil/mL • Total >40 mil • Motility >50% forward/25% rapid • Morphology >30%* >14%** • WBC <1 mil/mL *WHO, 1992 **Kruger Strict Criteria, 1999

  6. Sperm Density J Urol 1951; 66(3): 436

  7. Sperm Morphology features as a Prognostic Factor in IVF Kruger TF et al. Fertil Steril 1986; 46: 1118

  8. 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

  9. Male Factor Treatment Pregnancy rate results from RCT • Bromocriptine • 4 trials • OR 0.7, 95% CI 0.15-3.24 • Androgen therapy • 11 trials, n=930 • OR 1.1, 95% CI 0.75-1.61 • Clomiphene citrate • 10 trials, n=738 • OR 1.56, 95% CI 0.99-2.19 Cochrane Reviews 2003

  10. Need 1 million motile sperm Prefer > 5 million motile Little benefit >10 million motile IUI vs Timed Coitus Meta-analysis 17 RCT, n=3662 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 IUI Cochrane Reviews 2003

  11. Male age Female age 12-months 6-months Evidence for declining fertility in older men Ford et al. Hum Reprod, 2000 • 8515 planned pregnancies • Large population study questionnaire • Gestations >24 weeks

  12. 12-months Male age Female age 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

  13. Outcome rates and male age in 1023 donor oocyte cycles. Frattarelli in press, 2007

  14. P<0.05 P<0.05 P<0.05 Outcome rates and male age in 1023 donor oocyte cycles. Frattarelli in press, 2007

  15. Maternal age Couple age and Miscarriage rate de La Rochebrochard and Thonneau, Hum Reprod 2002 • N=3174 • 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

  16. P<0.05 P<0.05 Outcome rates and male age in 1023 donor oocyte cycles. Frattarelli in press, 2007

  17. The impact of paternal age on aneuploidy rates in first trimester losses • Controls = IVF patients using autologous oocytes (n=23) • Mean female age = 28.7 ± 1.1 • Mean male age = 33.7 ± 7.6 • Donor oocyte group (n=50) • 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

  18. 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 >20 disorders associated with paternal age • Alpert, Crouzon, Pfeiffer, Marfan, Achrondoplasia, neurofibromatosis, osteogenesis imperfecta

  19. Women have ~24 divisions in the cells that give rise to their eggs Men have >30 rounds of mitosis prior to puberty About 23 replications per year Meiosis vs Mitosis

  20. ~23 replications per year Age 30 380 mitotic divisions Age 40 610 mitotic divisions Age 50 840 mitotic divisions 2n Primary Spermatocyte Meiosis I n n Secondary Spermatocyte Meiosis II n n n n Spermatids n n n n Normal Sperm Spermatogenesis

  21. 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

  22. 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

  23. 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

  24. DNA damage in sperm • N=66 • Ages 20-57 • Gradual increased in DNA damage • Most pronounced after age 35 • ?Apoptosis decreases with age? Singh et al. Fertil Steril 2003

  25. Influence of Paternal Age on Down Syndrome • Incidence from 1983-1997 • N =3419 cases • NY state DOH congenital malformations registry • No paternal influence until >35 years • Paternal age contributes 50% risk Fisch et al. J Urol 2003

  26. Schizophrenia 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 >50 years -Israeli psychiatric registry -Controlled for age of other parent -Also for sex, ethnicity, and education Malaspina et al. Arch Gen Psychiatry 2001

  27. PAR1 SRY RPS4Y ZFY Yp YRRM1 Yq11 YRRM1, YRRM2 DAZ AZF region Yq Yq12

  28. 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 PAR1 SRY RPS4Y ZFY Yp YRRM1 YRRM1, YRRM2 DAZ AZF region Yq11 Yq Yq12 Microdeletions Brandell et al. Hum Repro 1998

  29. Microdeletions • N=5000 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

  30. Intracytoplasmic Sperm Injection (ICSI)

  31. 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 Klinefelter’s mosaics Consider karyotyping all infertile males? Consider prenatal diagnosis for all ICSI-derived pregnancies? ICSI-Derived Offspring

  32. 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

  33. Summary • Male aging • Decreased spermatogenesis • Decreased fertility • Increased miscarriage risk • Increased aneuploidy rates

  34. 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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