Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

East Meets West in Medicine

1,360 views

Published on

There I go again, a Western guy giving a lecture to an Eastern crowd. What team do I play on, you ask? In fact, I am honored to give a keynote at the First Integrative Fertility Symposium in Vancouver. Ok, call me a “swingman,” but the Easterners have a lot up their medical sleeves too. Ask Western medicine how to help a guy relax, and they’ll say, “don’t work so hard and take this pill.” Ask an Easterner, and they might suggest acupuncture, mindfulness and meditation. Which approach is better: a patch or a fix? You decide. Read more on my blog at > http://bit.ly/1EMuRFF

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

East Meets West in Medicine

  1. 1. A Planetary View of Men’s Reproductive Health Paul J. Turek MD, FACS, FRSM Beverly Hills and San Francisco
  2. 2. •Neither I, nor any member of my immediate family, have financial relationships to disclose relevant to the content of this presentation. •I will not discuss off-label use of any drug or therapy. Disclosures
  3. 3. Case •32 yo with 2 years of primary infertility. •Wife is 30 yo and healthy. Reg cycles. Prior TAB at age 25 yo. •He is “healthy:” takes no medications, no vices. •He has mild ED and low libido. •Semen analysis: 1.4 mL 10 million sperm/mL 20% motility Poor morphology •They proceed to IUI for 3 cycles and then conceive with IVF-ICSI
  4. 4. Sexual Health Overall Health Traditional World View Of Men’s Health
  5. 5. Sexual Health Sexual health issues are intimately related to overall health The Turek Clinic Worldview Of Men’s Health Overall Health
  6. 6. Case Cont. •1 year later, he presents with visual changes. •Diagnosed with prolactinoma. •Infertility may reflect disease.
  7. 7. Reasons to Evaluate Male Infertility 1. Enables infertility to be cured, not bypassed. 2. Allows discovery of potential underlying medical conditions (i.e. infertility as a “natural biomarker”) 3. May be a “window” into future health.
  8. 8. Erectile Dysfunction and Overall Health 1. ED and heart disease involve endothelial cell dysfunction. 2. ED is a marker of silent cardiac and vascular disease. 3. ED predicts occurrence of significant cardiovascular events 5-10 years later.
  9. 9. History Physical Exam Semen Analysis x 2 Eliminate GonadotoxinsFurther Female Evaluation AbnormalNormal Abnormal Normal Treat Female Factor Focused Further Evaluation Not Improved Improved Hormone Evaluation Treat Female Factor Male Evaluation Sequence Turek. Nat Clin Prac. 2: 1, 2005
  10. 10. Reproductive and Overall Health Medical conditions associated with male infertility and sexual dysfunction: Obesity Heart disease (ED) Diabetes Varicocele Undescended testicle Anabolic steroid use Chronic opiate use Myelodysplasia Multiple sclerosis Organ failure: liver, renal failure; thyroid Hemachromatosis Sickle cell anemia/B thalassemia Metabolic syndrome (ED) Congenital adrenal hyperplasia Syndromes: Noonan, myotonic dystrophy, gonadal dysgenesis, Young. Prune belly, 5- alpha-reductase deficiency Wet heat exposure Smoking; recreational drugs Medications: antiandrogens; sulfa agents; Ca+ channel blockers; alpha blockers Autosomal dominant polycystic kidney (ADPK) Sexually transmitted diseases Benign prostatic hypertrophy Occupational exposures, heat, benzene, creosote Industrial toxins: Dioxin, PCBs, bisphenol A Lower general health status
  11. 11. Reproductive and Overall Health Medical conditions that cause male infertility Y chromosome deletions Karyotype anomalies (e.g., Klinefelter syndrome) Congenital absence of the vas deferens (CAVD) Hypogonadotropichypogonadism Surgical procedures: TURP, vasectomy, orchiectomy, hernia repair Testis cancer Cancer treatment Kartagener syndrome Mumps orchitis Prolactinoma Androgen receptor defects Infections—epididymitis Impotence Spinal cord injury
  12. 12. Reproductive and Overall Health Medical conditions that cause erectile dysfunction Heart disease Diabetes Multiple sclerosis Dyslipidemia Hypogonadism Prolactinoma/emia Medications Peyronie disease Surgery: radical prostatectomy or cystectomy, TURP, penile surgery Trauma/injury: penile fracture, AVM, spinal cord injury Medical conditions linked to a history of male infertility Testis cancer Prostate cancer Medical conditions linked to a history of ED Heart disease/MI/peripheral vascular disease BPH/voiding dysfunction
  13. 13. Infertility Obesity StressMedications Heart Disease Diabetes Cholesterol Prolactin Surgery Injury Organ Failure Low Testosterone High Blood Pressure Sleep The Usual Suspects… Alcohol & Drugs
  14. 14. Men’s Reproductive Health as a Window to Overall Health 1. Male infertility and the later development of testis cancer. 2. Male infertility and the later development of prostate cancer.
  15. 15. DNA mutations are a fact of life • Constant challenges – Chemical – Irradiation – Physical • Organisms have developed an intricate network of DNA repair systems. • DNA repair mechanisms are more “taxed” in germ cells
  16. 16. Systems Insure High Fidelity Transmission of DNA to Next Generation • DNA polymerase • Nucleotide excision repair (NEC) • DNA mismatch repair (MMR genes)
  17. 17. Abnormalities in DNA Repair In animal models: – More tumors. Also seen in humans with non-polyposis colon cancer (HNPCC), retinoblastoma and skin cancer. – Infertility. Mice with mutations in MMR genes exhibit infertility. True in humans? Chaganti and German. Am J Hum Gen. 31: 634, 1979
  18. 18. Transgenic Mice with DNA Mismatch Repair Gene Defects are Infertile The Mice Papers Baker S et al. Cell. 82: 309, 1995 Edelmann et al. Cell. 85: 1125, 1996
  19. 19. Mice Phenotype= Human Infertility Phenotype Mouse Human
  20. 20. Is There Evidence of Faulty DNA Repair in Infertile Men? Mouse Man •6 infertile men with azoospermia and maturation arrest. •5 infertile men with normal spermatogenesis. •Examined blood and testis tissue for microsatellite instability at polymorphic marker D19S49 on 19q12. Nudell D et al. Hum Reprod.15: 1289, 2000.
  21. 21. %CloneswithPointMutations EARLY ARREST LATE ARREST NORMAL 2 19 31 5 34 100 500 600436 11 17 Infertile Patients Nudell D. Hum Reprod.15: 1289, 2000. Polymorphic Marker: D19S49 Human mean = 9% Mice Mlh1-/- =14%
  22. 22. What Does This Mean? Is there a larger reason to be infertile? DNA repair failure results in infertility. Male germ line responsible for mutations and evolution. Is this the ultimate “medical disease” of a species?
  23. 23. Infertility Phenotype Suggested Taking a Closer Look at Meiotic Recombination Centromeres-blue; SCP-red; MLH1-yellow Gonsalves et al, 2004 Sun et al, 2006
  24. 24. Is There Defective Recombination in Infertile Men? Normal Obstr Hypo MatArr Pachytene Spread MLH1 Foci Yes Gonsalves et al, 2004
  25. 25. •There are abnormalities of chromosomal pairing in azoospermic men. Sun et al. Cytogenet Genome Res. 111: 366, 2005 •Recombination errors show distinct patterns among chromosomes. Sun et al. Cytogenet Hum Reprod. 15: 2376, 2006 •Localization patterns of 5 meiotic proteins well studied. MSH4 appears to stabilize recombination. Oliver Bonet et al. Mmol Hum Reprod. 11: 517, 2005 Other Facts About Recombination in Infertile Men
  26. 26. Time Meiosis Mitosis What’s Going on with Sperm? Things Happen Faster and More Frequently in the Testis Phenotypic change
  27. 27. Male Infertility and Cancer Do Infertile Men Have Higher Rates of Cancer? 51,000+ infertile males • 15 California centers • 1965 to 1998 California Cancer Registry (CCR) • 10 SEER Regions 1973 to 2003 – Testis cancer – Prostate cancer – Colon cancer – Melanoma  Walsh et al. Arch Int Med. 169: 351, 2009 Walsh et al. Cancer. Epub. Mar 2010
  28. 28. Do Infertile Men Have Higher Rates of Subsequent Testis Cancer? Incidence of testis cancer rising over last 3-5 decades •3.8 to 6.8 cases/100k person-years in US (1975-2002) •3.5 to 10 cases/100k person-years in Norway (1960-2000) Cohort studies demonstrate increased risk •Jacobsen et al, 2000 (Denmark) showed SIR of 1.6 (CI, 1.3-1.9) •Raman et al, 2005 (U.S) showed SIR 18.3 (CI, 18-18.8) Conclusions •Is the association described in European men true for US men? •Is the true risk of testis cancer well described in US infertile men?
  29. 29. Infertility and Subsequent Testis Cancer METHODS 51, 461 couples 42, 274 men (82%) CCR linkage 22, 252 men (44%) Complete data 14, 557 men (76%) No male factor 4549 men (24%) With male factor •Multi-institutional, California •15 infertility centers (1967-98) •Male infertility defined by abnormal WHO semen parameters •Linked to Cal Cancer Registry (CCR). Contains all SEER registeries •>1year between infertility and cancer diagnosis
  30. 30. Age-Aggregated Standardized Incidence Ratios (SIR) and 95% CIs for Testicular Cancer in Men with and without Male Factor Infertility Walsh et al, Arch Int Med. 169: 351, 2009
  31. 31. Do Infertile Men Have Higher Rates of Subsequent Prostate Cancer? Prostate cancer is the most common malignancy in US men Risk factors for prostate cancer include •Age •Family history •Race (African American) Fatherhood has also been proposed as a risk factor •Jorgensen et al, 2008: Childless men less likely to have prostate cancer. Cancer risk declines with more children. •Giwercman et al, 2005: Being childless was protective for prostate cancer [OR 0.83, CI 0.81-0.86] •Negri et al, 2006: Being childless was not protective for prostate cancer [OR 0.95, CI 0.73-1.24] •Ruhayel et al, 2010: Infertile men have a significantly reduced risk of prostate cancer [OR 0.55, CI0.25-0.83]
  32. 32. Infertility and Subsequent Prostate Cancer METHODS 51, 461 couples 42, 274 men (82%) CCR linkage 22, 262 men (44%) Complete data 14, 557 men (76%) No male factor 4549 men (24%) With male factor •Multi-institutional, California •15 infertility centers (1967-98) •Male infertility defined by abnormal WHO semen parameters •Linked to Cal Cancer Registry (CCR). Contains all SEER registeries • >1year between infertility and cancer diagnosis
  33. 33. Age-Aggregated SIR’s for Prostate Cancer Among 22,562 Men Evaluated for Infertility Walsh et al. Cancer. Epub. Mar 2010 Fertility Status # Men # Cancers SIR (95%CI) All cancers Male Factor Infertility No 14,557 64 0.7 (0.6-0.9) Yes 4,549 56 1.3 (1.0-1.7) Low-grade cancers (Gl 5-7) Male Factor Infertility No 14,557 47 0.7 (0.6-1.0) Yes 4,549 37 1.2 (0.8-1.6) High-grade cancers (Gl 8-10) Male Factor Infertility No 14,557 16 0.8 (0.5-1.3) Yes 4,549 19 2.0 (1.2-3.0)
  34. 34. Infertility and Subsequent Prostate Cancer RESULTS Examined cancer risk in infertile men using multivariate Cox proportional hazards regression: Adjusted model*: Men with male factor infertility were 2.6 fold more likely to be diagnosed with high grade prostate cancer *Adjusted for: age, duration of infertility, treatment facility Walsh et al. Cancer. Epub. Mar 2010
  35. 35. Men’s Reproductive Health: Overall Health Salonia A et al. Eur Urol. 2009, 56: 891 Methods: • Charleston CoMorbidity Index • Compared infertile and fertile men. Hypothesis: men with male factor infertility have a higher rates of disease (other than cancers) when compared with the general, fertile population.
  36. 36. Men’s Reproductive Health: Overall Health Jensen TK et al. Am J Epid. 2009, 170: 559 Methods • Large, population based study from Copenhagen • Semen quality examined in 43,277 fertile and infertile men. • Men followed for 38 years! Results • Clear association between sperm counts and death rates. • Men with highest sperm counts had 43% lower death rates than those with lowest counts.
  37. 37. Men’s Reproductive Health: Overall Health Eisenberg et al. Hum Reprod. 2014, 29:1567. Epub May 15. Methods • Epidemiological study in Texas and California • Correlated semen quality and death rates in 11, 935 men over 12-years Results • Over a 7.7-year period, 0.58% of men died. • This death rate much lower (by 60%) than general population. • However, men with two or more semen abnormalities were 2.3 times more likely to die than those without abnormalities.
  38. 38. Men’s Reproductive Health: Infertility 1. Male infertility is associated with the later development of cancer. 2. Male infertility is associated with reduced overall health and possibly higher mortality. 3. Male infertility is certainly an important disease or marker of disease!!
  39. 39. Infertility Obesity StressMedications Heart Disease Diabetes Cholesterol Prolactin Surgery Injury Organ Failure Low Testosterone High Blood Pressure Sleep The Usual Suspects… Alcohol & Drugs
  40. 40. Male Infertility: Marker of Disease Thanks to: Uche Ezeh M.D. Mark Fox Ph.D Shai Shefi M.D. Amander Clark Ph.D Renee Reijo Pera Ph.D Jeff Simko M.D. Thomas Walsh MD, MS Nina Kossack Ph.D David Nudell MD Mary Croughan Ph.D NIH; CIRM Lance Armstrong Foundation California Urology Foundation

×