Acquired Disorders of Spermatogenesis By Paul J. Turek MD, Emeritus Professor and Endowed Chair in Urology Education, Department of Urology, University of California San Francisco and Director of the The Turek Clinic

Acquired Disorders of Spermatogenesis Paul J. Turek M.D.Emeritus Professor and Endowed Chair in Urology Education,Department of Urology, University of California San Francisco, Director, The Turek Clinic

Acquired Disorders of Spermatogenesis Learning Objectives 1.  Describe the hormonal basis for opioid endocrinopathy 2.  Name 2 drugs that act as antiandrogens 3.  Delineate the changes in semen parameters ascribed to 5-alpha reductase inhibitors 4.  Explain how physical stress affects sex hormones

Male Evaluation History Sequence Physical Exam Medical and Surgical Hx Medications Social Hx Occupational Hx Semen Analysis x 2 Normal Abnormal Further Female Evaluation Eliminate Gonadotoxins Not Abnormal Normal Improved Improved Treat Female Hormone Treat Female Factor Evaluation Factor Focused Turek. Further Nat Clin Prac. Evaluation 2:1, 2005

The Medical Medical Surgical & Surgical Infection Hernia History Trauma Trauma CF Diabetes, Pelvic/Bladder Multiple sclerosis, Retroperitoneal Cord injury TURP Cancer XRT Orchidopexy Fevers Mumps Torsion Diabetes

Acquired Medical Conditions Presenting as Infertility Pituitary Tumors-prolactinoma Retroperitoneal tumors Diabetes mellitus Testis or other cancer 1-10% Multiple sclerosis Honig SC, Lipshultz LI, Jarow J. Fertil Steril. 62(5):1028, 1994

Case study25 yo male married to 25 yo healthy woman.1 year of primary infertility, decreased libidoPhysical Exam: 15cc testes bilaterallySemen Analysis: AzoospermiaTestis biopsy: Maturation arrestHormones: Total Testosterone: 75 ng/mL (260-1000) FSH 1.2 IU/mL (2-8) LH 1.5 IU/mL (2-12) Prolactin 265 ng/mL (1-24)

Medications and Male Infertility Name EffectKetoconazole (prostate cancer) Impaired spermatogenesisCimetidine Impaired spermatogenesisSaw palmetto ?Antiestrogen effectHerbal supplements ?Estrogenic activityTricyclic antidepressants Sexual dysfunctionSSRI’s Sexual dysfunction; elevated prolactinNitrofurantoin Impaired spermatogenesis, mat. arrestErythromycin Impaired spermatogenesis, motilityTetracyclines ?Impaired motilitySulfa antibiotics Impaired spermatogenesisColchicine Impaired fertilizationAllopurinol Impaired fertilizationSulfasalazine Impaired spermatogenesis, motilityAnabolic steroids Suppress H-P-G axisTestosterone replacement Suppress H-P-G axis

The Opioid Endocrinopathy• Naturally occuring opiates (endorphins) reduce T levels by reducing GnRH levels and pituitary drive (hypogonadotrophic hypogonadism)• 74% of n=54 men taking daily sustained action oral opiates had low testosterone levels. Daniel HW. J Pain. 2002, 3:377• 100% of men taking 100mg methadone daily had low T levels. Daniel HW. J Pain. 2002, 3:377• Observed in men taking intrathecal and transderm opiates. Mean decrease T in 10 men on intrathecal opiates: Baseline 7.7 nmol/L fell to 2 nmol/L on therapy. Roberts et al. Clin J Pain. 2002, 18:144• 85% of men on intrathecal opiates have low T levels. Abs et al. JCEM. 2000, 85:2215

Antihypertensives and Male InfertilityDrug Name EffectThiazides Decrease penile blood flowB-blockers Decrease libido and EDCa+ channel blockers Impairs acromosome Rxn, fertilizationSpironolactone Anti-androgen, impaired spermatogenesisAlpha blockers Retrograde ejaculationACE inhibitors No demonstrated effect

Chemotherapy affects Spermatogenesis: Quantity 100 90 80 70 Pre-Rx% Oligo 60 or Azo Post-Rx 50 40 30 20 10 0 Stage 1 Stage 3 Lymph Osteo Sarcoma Leukemia Testis Ca Sarcoma Turek PJ. Fertility Preservat. in Males with Cancer, 2002

Which chemotherapeutic agents are the worst for infertility?Agent Spermato- Spermato- Spermatids Sertoli cells gonia cytesCisplatin +++ ++ + +Cyclophosphamide +++Adriamycin +++ ++ + +Vinblastine +++ +++ +++

Genotoxicity: Sperm Aneuploidy with Chemotherapy The image cannot be displayed. Your Hodgkins Disease computer may not have enough memory 200 to open the image, or the image may have been corrupted. FISH on chromos: X, Y, 8 Restart your computer, and then open the ﬁle again. If the red x still appears, you may have to delete the image and then insert it again. 150Hyperhaploid sperm 100 50 0 -100 0 100 200 300 NOVP Days CHEMO WA Robbins et al. Nat Genet. 16: 74-78, 1997

A Problem with Sperm Banking with Cancer: Patient and Provider Attitudes PROVIDERS PATIENTSSurvey of 718 oncology staff 904 men with cancerTwo tertiary cancer centers Two tertiary cancer centers91% believed banking should be offered 51% wanted future fertility52% actually offered it to patients 60% recall being informedReasons: high cost, convenience 24% banked sperm Reasons: Lack of information Serious room for improvement: Practice standards? Team medicine? Schover et al. J Clin Oncol. 20:1880, 2002 Schover et al. J Clin Oncol. 20:1890, 2002

Facts about Inflammatory Bowel DiseaseWhat do we know about male fertility effects of IBD drugs?Drug Count Motility Morphology Birth DefectsSulfasalazine Yes Yes Yes Possibly Moody et al. Int J Colorectal Dis. 12:220-4, 1997Mesalamine No No No None Kjaergaard N et al. Scand J Gastroenterol 24:891-6, 1989Azathioprine ?No ?No ?No 7.4% vs 4.4%6-mercaptopurine Reinisch W. Gastroenterol 121:1048-1053, 2001 Dejaco C and Norgard B et al. Aliment Pharmacol Ther 19: 679-85, 2004

How Toxic are “Milder Forms of Chemotherapy?• Infliximab-monoclonal antibody to tumor necrosis factor (TNF) alpha. A form of immunotherapy for inflammatory bowel diseases.• Prospective, case-controlled analysis of 2 cohorts.• Each patient served as their own control. I Maintenance II Naive Mahadevan et al. Inflamm Bowel Dis.2005, 11: 395

Infliximab and Semen Quality: ResultsSemen Quality Pre/Post Infusion: Maintenance (n=7) Mahadevan et al. Inflamm Bowel Dis.2005, 11: 395

Results Semen Quality Pre/Post Infusion: Naive (n=3)Parameter Pre-Infusion Post-InfusionCDA Index 210 187 (<150)Volume (mL) 4.4 4.9Concentration (mill/mL) 76 80% Motility 53% 41% (p=.12)Progression (1-4) 2.6 2.9Total Motile Count 154 million 134 millionNormal Oval Forms (%) 9.5 9.7

How Toxic are “Milder Forms of Chemotherapy?• Azathioprine/6-Mercaptopurine (AZA/6MP) is another effective chemotherapy Rx for IBD.• AZA/6MP may lead to genetic damage that results in infertility and congenital malformations.• Basic semen analysis may be inadequate to determinedamage to sperm from AZA/6MP.• Study:Compare rates sperm DNA damage among menwith IBD exposed and unexposed to AZA/6MP. Mahadevan et al. 2007

AZA/6MP Effects on Semen ParametersMean values Unexposed Exposed T-test[WHO normal] N= 11 (range) N=17 (range) P-valueDays abstinent 3.32 (2.0, 4.5) 3.4 (2.0, 6.5) 0.84Volume [1.5-5 ml] 2.7 (1.3, 4.8) 3.4 (1.1, 6.3) 0.16Concentration 71.8 (25.5,155) 65.7 (5.5,140) 0.71[>20 mln/ml] Motility [>50%] 63% (40, 80) 53% (41,66) 0.005Progression [1-4] 2.9 (2.38, 3.5) 2.64 (1.8, 3.3) 0.13Total Motile Count 102.1 (50, 141) 106.5 (8, 231) 0.83[>40million] Normal oval forms [>14%] 7.5% (1.5,12.5) 6.0 % (0,14) 0.37

AZA/6MP Effects on Sperm DNASample #2 Unexposed Exposed PMean values N= 9 (range) N=16 (range) valueDFI (%) 9.1% (3.9,14.7) 13.9% (3.7,31.6) 0.071< 15% excellent 9 excellent 11 excellent 0.123>15 to <30% good 4 good>30% fair to poor 3 fair-poorHDS 5.6% 7.71% 0.17[<15% = normal] (4-8.7) (3.1-22.9) No obvious effect on semen parameters. Mild DFI effect? Sperm quality control is impressive.

Suspect Medications? Name EffectFinasteride (1 or 5mg) Impaired spermatogenesis?HMG-CoA reductase inhibitors Alters cholesterol, ?infertilityPDE5 inhibitors Altered motility?

5-alpha Reductase Inhibitors and Male Infertility • Case reports suggest impairments in count, motility and volume. Liu et al. Fert Steril, 2007 Epubl • Randomized controlled trial showed confirms changes in volume and sperm count and also showed reversibility (n=99 men; 1 yr Rx) Amory et al. JCEM. 2007, 92:1659Parameter Finasteride Dutasteride 6mos 12 mos 6 mos 6mos 12 mos 6 mosVolume 15%* 23% 30%* 6%Total count 29%* 16% 34%* 25%Motility 6-12% 6-12%Morphology No effect No effect

HMG-CoA reductase inhibitors and Male InfertilityNo effect in rats after 11 weeks on: reproductive organweights, epididymal sperm counts, motility and standardfertility indices. Dostal et al. Fundem Appl Toxicol 1996, 32: 285No effect in beagle dogs after 1 year on: reproductive organweights, semen volume, concentration, motility or morphology.Fertility not studied. Dostal et al. Toxicol Sci, 2001, 61-128

PDE5 Inhibitors and Male Infertility• Sperm incubated with sildenafil in vitro: Increase in progressive motility and hyperactivation by CASA. Also +/-50% increase in acrosome reaction. Cuadra et al. Am J Ob Gyn. 2000, 182:1031 Glenn et al. Fert Steril. 2007, 87:1064 Lefievre et al. J Androl. 2000, 21:929• Motility in ejaculated sperm from infertile men (n=18) examined 1-2 hrs after treatment with either sildenafil or tadenifil. Sildenafil 28% to 37% Tadenafil 28% to 22% Pomara et al. Fert Steril. 2000, 88:860• Studies in men treated with daily vardenafil demonstrate more total sperm numbers and improved motility. Postulated mechanism is increased prostate secretions? Dimitriadis et al. Asian J Androl. 2008, 10: 115

Habits ExposuresETOH HeatTobacco StressMarijuana PesticidesCocaine Lead Radiation

Habits and Male Infertility

Habits and Male Infertility• Tobacco1.  Associated with lower sperm concentration and motility2.  Associated with increased seminal leukocytes.3.  Decreased libido and ED, Lower GnRH, LH and T. impairs erections in high doses.

• N=11 infertile men• Wet heat discontinued (tubs, baths, Jacuzzis)• Followed for 6 months•  5 men “responded” with TMC increase of 491%• Mainly motility (12% to 34%)• Smokers tended not to respond

Stress and Male InfertilityLots of opinions….. “Mild-to-severe emotional stress depresses testosterone and perhaps interferes with spermatogenesis in the human male.” McGrady AV, Arch Androl 1984, 13:1 “The majority of studies reject the theory of stress as a lone factor in the etiology of infertility. However, there is growing evidence that stress stands as an additional risk factor for infertility.” Schneid-Kofman et al. Med Sci Monit 2005, 11:8.

Effect of Extreme Physical Stress on LH and T • N=10 male soldiers [mean 22 yr] • Blood drawn every 20 min over night: After a “control” week After 84 hrs of military “operational” stress that included: Physical: Continuous combat drills, marches Sleep: 2 x 1 hrs/day Caloric: 1 meal, 1 snack/day Mean LH level over 12 hrsResults:46% increase in LH levels with stress (but with increased burst interval)24% lower T and 30% lower Free T levels with stressSuggests decreased testis B. C. et al. J Appl Physiol 100:with stress Nindl, sensitivity to LH 120-128 2006; doi:10.1152/japplphysiol.01415.2004 Nindl et al.Copyright ©2006 American Physiological Society 2006, 100:120

Simple RxFor Stress

BMI and Male Infertility• Obese men have more trouble achieving pregnancies. Danish cohort study of 26,303 planned pregnancies. Adjusting for partner BMI, coital frequency, ages and smoking habits et al. Hum Reprod.2007, 22: 2488 Nguyen BMI OR of infertility (CI) <25.5 1 25-30 1.2 1.04-1.38 30-35 1.36• Obese men have lower sperm counts and motilities. 1.13-1.63 Utah cohort study of 526 infertile men. BMI <25 5.3% oligospermia Hammoud et al BMI 25-30 9.2% oligospermia Fert Steril. BMI >30 15.6% oligospermia Epub Jan 2008

Indications for Varicocele Repair1. Adolescent-large lesion and atrophy2. Adolescent/adult-pain3. Male factor infertility with adequate maternal potential (>1 year) Mean=8mos4. Male factor infertility with azoospermia.

Acquired Disorders of Spermatogenesis Summary•  Many substances, exposures and lifestyles issues can affect male infertility. Most data is acquired “in the field’ with use.•  Many fewer substances have been shown to impair spermatogenesis. Evidence is generally Level III at best. Turek Fert Steril 2008

Acquired Disorders of Spermatogenesis Examination Question Which of the following drugs is known to impair spermatogenesis by reducing by causing hypogonadotrophic hypogonadism? a.  Spironolactone, an antiandrogen b.  Calcium channel blockers, antihypertensives c.  5-alpha reductase inhibitors d.  Chronic opiate use Answer:

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Acquired Disorders of Spermatogenesis By Paul J. Turek MD, Emeritus Professor and Endowed Chair in Urology Education, Department of Urology, University of California San Francisco and Director of the The Turek Clinic

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Acquired Disorders of Spermatogenesis By Paul J. Turek MD, Emeritus Professor and Endowed Chair in Urology Education, Department of Urology, University of California San Francisco and Director of the The Turek Clinic — Presentation Transcript