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 Sequence

History Physical Exam

Medical and Surgical Hx Medications Social Hx Occupational Hx

Semen Analysis x 2 Normal Further Female Evaluation Abnormal Treat Female Factor Normal Abnormal Eliminate Gonadotoxins Not Improved Hormone Evaluation Focused Further Evaluation Improved Treat Female Factor

Turek. Nat Clin Prac. 2:1, 2005

The Medical & Surgical History

Medical Infection Trauma CF Diabetes, Multiple sclerosis, Cord injury

Surgical Hernia Trauma

Pelvic/Bladder Retroperitoneal TURP

Cancer XRT Fevers Mumps Torsion Diabetes

Orchidopexy

Acquired Medical Conditions Presenting as Infertility

Pituitary Tumors-prolactinoma Retroperitoneal tumors Diabetes mellitus Testis or other cancer Multiple sclerosis

1-10%

Honig SC, Lipshultz LI, Jarow J. Fertil Steril. 62(5):1028, 1994

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: FSH LH Prolactin 75 ng/mL (260-1000) 1.2 IU/mL (2-8) 1.5 IU/mL (2-12) 265 ng/mL (1-24)

Medications and Male Infertility

Name
Ketoconazole (prostate cancer) Cimetidine Saw palmetto Herbal supplements Tricyclic antidepressants SSRIs Nitrofurantoin Erythromycin Tetracyclines Sulfa antibiotics Colchicine Allopurinol Sulfasalazine Anabolic steroids Testosterone replacement

Effect
Impaired spermatogenesis Impaired spermatogenesis ?Antiestrogen effect ?Estrogenic activity Sexual dysfunction Sexual dysfunction; elevated prolactin Impaired spermatogenesis, mat. arrest Impaired spermatogenesis, motility ?Impaired motility Impaired spermatogenesis Impaired fertilization Impaired fertilization Impaired spermatogenesis, motility Suppress H-P-G axis 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 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

Chemotherapy affects Spermatogenesis: Quantity

100 90 80 70 % Oligo 60 or Azo 50 40 30 20 10 0

Pre-Rx Post-Rx

Stage 1 Stage 3 Lymph

Testis Ca

Osteo Sarcoma Leukemia Sarcoma

Turek PJ. Fertility Preservat. in Males with Cancer, 2002

Which chemotherapeutic agents are the worst for infertility?

Agent

Spermatogonia +++ +++ +++ +++

Spermato- Spermatids Sertoli cells cytes ++ ++ +++ + + +++ + +

Cisplatin Cyclophosphamide Adriamycin Vinblastine

Genotoxicity: Sperm Aneuploidy with Chemotherapy

200 150 Hyperhaploid sperm 100 50 0 -100
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Hodgkins Disease FISH on chromos: X, Y, 8

NOVP CHEMO

100 Days

200

300

WA Robbins et al. Nat Genet. 16: 74-78, 1997

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

What do we know about male fertility effects of IBD drugs? Drug
Sulfasalazine

Count Motility Morphology Birth Defects

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

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: Results

Semen 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
CDA Index Volume (mL) % Motility Progression (1-4) Total Motile Count Normal Oval Forms (%)

Pre-Infusion
210 4.4 53% 2.6 154 million 9.5

Post-Infusion
187 4.9 80 41% (p=.12) 2.9 134 million 9.7 (<150)

Concentration (mill/mL) 76

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

AZA/6MP Effects on Semen Parameters

Mean values
[WHO normal]
Days abstinent
Volume [1.5-5 ml]
Concentration
[>20 mln/ml]
Motility [>50%]
Progression [1-4]
Total Motile Count [>40million]
Normal oval forms [>14%]

Unexposed N= 11 (range) 3.32 (2.0, 4.5) 2.7 (1.3, 4.8) 71.8 (25.5,155) 63% (40, 80) 2.9 (2.38, 3.5) 102.1 (50, 141) 7.5% (1.5,12.5)

Exposed N=17 (range) 3.4 (2.0, 6.5) 3.4 (1.1, 6.3) 65.7 (5.5,140) 53% (41,66) 2.64 (1.8, 3.3) 106.5 (8, 231) 6.0 % (0,14)

T-test P-value 0.84 0.16 0.71 0.005 0.13 0.83 0.37

AZA/6MP Effects on Sperm DNA

Sample #2 Mean values DFI (%) Unexposed N= 9 (range) 9.1% (3.9,14.7) Exposed N=16 (range) P value

13.9% (3.7,31.6) 0.071 11 excellent 4 good 3 fair-poor 7.71% (3.1-22.9) 0.123

< 15% excellent 9 excellent >15 to <30% good >30% fair to poor HDS [<15% = normal] 5.6% (4-8.7)

0.17

No obvious effect on semen parameters. Mild DFI effect? Sperm quality control is impressive.

Suspect Medications?
Name Effect Finasteride (1 or 5mg)
HMG-CoA reductase inhibitors PDE5 inhibitors

Impaired spermatogenesis? Alters cholesterol, ?infertility 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, 92:1659 Parameter Volume Total count Motility Morphology Finasteride 6mos 12 mos 6 mos 15%* 23% 29%* 16% 6-12% No effect Dutasteride 6mos 12 mos 6 mos 30%* 6% 34%* 25% 6-12% No effect

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

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
ETOH Tobacco Marijuana Cocaine

Exposures
Heat

Stress
Pesticides Lead Radiation

Habits and Male Infertility

Tobacco

Habits and Male Infertility

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.

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 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.

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 Nindl, Suggests decreased testis B. C. et al. J Appl Physiol 100:with stress sensitivity to LH 120-128 2006; doi:10.1152/japplphysiol.01415.2004
Copyright 2006 American Physiological Society

Nindl et al. 2006, 100:120

Simple Rx For 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 BMI 25-30 BMI >30 5.3% oligospermia 9.2% oligospermia 15.6% oligospermia
Hammoud et al Fert Steril. Epub Jan 2008

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.

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. b. c. d. Spironolactone, an antiandrogen Calcium channel blockers, antihypertensives 5-alpha reductase inhibitors Chronic opiate use

Answer: