Lecture on Acquired Disorders of Spermatogenesis written and presented by Paul J. Turek MD, Emeritus Professor and Endowed Chair in Urology Education, Department of Urology, University of California San Francisco and current Director of the The Turek Clinic, in San Francisco, California.

1. 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

2. 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

3. 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

4. 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

5. 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

6. Case study
25 yo male married to 25 yo healthy woman.
1 year of primary infertility, decreased libido
Physical Exam: 15cc testes bilaterally
Semen Analysis: Azoospermia
Testis biopsy: Maturation arrest
Hormones:
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)

7. Medications and Male Infertility
Name Effect
Ketoconazole (prostate cancer) Impaired spermatogenesis
Cimetidine Impaired spermatogenesis
Saw palmetto ?Antiestrogen effect
Herbal supplements ?Estrogenic activity
Tricyclic antidepressants Sexual dysfunction
SSRI’s Sexual dysfunction; elevated prolactin
Nitrofurantoin Impaired spermatogenesis, mat. arrest
Erythromycin Impaired spermatogenesis, motility
Tetracyclines ?Impaired motility
Sulfa antibiotics Impaired spermatogenesis
Colchicine Impaired fertilization
Allopurinol Impaired fertilization
Sulfasalazine Impaired spermatogenesis, motility
Anabolic steroids Suppress H-P-G axis
Testosterone replacement Suppress H-P-G axis

8. 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

9. Antihypertensives and Male Infertility
Drug Name Effect
Thiazides Decrease penile blood flow
B-blockers Decrease libido and ED
Ca+ channel blockers Impairs acromosome Rxn, fertilization
Spironolactone Anti-androgen, impaired spermatogenesis
Alpha blockers Retrograde ejaculation
ACE inhibitors No demonstrated effect

10. 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

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

12. Genotoxicity: Sperm Aneuploidy with Chemotherapy
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CHEMO
WA Robbins et al. Nat Genet. 16: 74-78, 1997

13. A Problem with Sperm Banking with Cancer:
Patient and Provider Attitudes
PROVIDERS PATIENTS
Survey of 718 oncology staff 904 men with cancer
Two tertiary cancer centers Two tertiary cancer centers
91% believed banking should be offered 51% wanted future fertility
52% actually offered it to patients 60% recall being informed
Reasons: 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

14. Facts about Inflammatory Bowel Disease
What do we know about male fertility effects of IBD drugs?
Drug Count Motility Morphology Birth Defects
Sulfasalazine Yes Yes Yes Possibly
Moody et al. Int J Colorectal Dis. 12:220-4, 1997
Mesalamine No No No None
Kjaergaard N et al. Scand J Gastroenterol 24:891-6, 1989
Azathioprine ?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

15. 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

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

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

18. 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 determine
damage to sperm from AZA/6MP.
• Study:Compare rates sperm DNA damage among men
with IBD exposed and unexposed to AZA/6MP.
Mahadevan et al. 2007

19. AZA/6MP Effects on Semen Parameters
Mean values
Unexposed Exposed T-test
[WHO normal]
N= 11 (range) N=17 (range) P-value
Days abstinent
3.32 (2.0, 4.5) 3.4 (2.0, 6.5) 0.84
Volume [1.5-5 ml]
2.7 (1.3, 4.8) 3.4 (1.1, 6.3) 0.16
Concentration
71.8 (25.5,155) 65.7 (5.5,140) 0.71
[>20 mln/ml]
Motility [>50%]
63% (40, 80) 53% (41,66) 0.005
Progression [1-4]
2.9 (2.38, 3.5) 2.64 (1.8, 3.3) 0.13
Total 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

20. AZA/6MP Effects on Sperm DNA
Sample #2 Unexposed Exposed P
Mean values N= 9 (range) N=16 (range) value
DFI (%) 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-poor
HDS 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.

21. Suspect Medications?
Name
Effect
Finasteride (1 or 5mg) Impaired spermatogenesis?
HMG-CoA reductase inhibitors Alters cholesterol, ?infertility
PDE5 inhibitors Altered motility?

22. 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, 92:1659
Parameter Finasteride Dutasteride
6mos 12 mos 6 mos 6mos 12 mos 6 mos
Volume 15%* 23% 30%* 6%
Total count 29%* 16% 34%* 25%
Motility 6-12% 6-12%
Morphology No effect No effect

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

24. 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

25. Habits Exposures
ETOH Heat
Tobacco Stress
Marijuana Pesticides
Cocaine Lead
Radiation

27. Habits and Male Infertility

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

29. • 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

30. Stress and Male Infertility
Lots 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.

31. 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 hrs
Results:
46% increase in LH levels with stress (but with increased burst interval)
24% lower T and 30% lower Free T levels with stress
Suggests 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

32. Simple Rx
For Stress

33. 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

34. Indications for Varicocele Repair
1. Adolescent-large lesion and atrophy
2. Adolescent/adult-pain
3. Male factor infertility with
adequate maternal potential (>1 year)
Mean=8mos
4. Male factor infertility with azoospermia.

35. 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

36. 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: