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

Acquired Disorders of Spermatogenesis

History Physical Exam

Semen Analysis x 2

Eliminate Gonadotoxins Further Female Evaluation

Abnormal Normal

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

Medical and Surgical Hx Medications Social Hx Occupational Hx

Medical

Infection Trauma CF

Diabetes, Multiple sclerosis, Cord injury

Cancer XRT Fevers Mumps Torsion Diabetes

Surgical

Hernia Trauma

Pelvic/Bladder Retroperitoneal TURP

Orchidopexy

The Medical & Surgical

History

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

Acquired Medical Conditions Presenting as Infertility

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)

Medications and Male Infertility

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

Name Effect

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.

• 100% of men taking 100mg methadone daily had low T levels.

• 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.

• 85% of men on intrathecal opiates have low T levels.

Daniel HW. J Pain. 2002, 3:377

Daniel HW. J Pain. 2002, 3:377

Roberts et al. Clin J Pain. 2002, 18:144

Abs et al. JCEM. 2000, 85:2215

Antihypertensives and Male Infertility

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

Drug Name Effect

Chemotherapy affects Spermatogenesis: Quantity

0

10

20

30

40

50

60

70

80

90

100

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

Post-Rx

Pre-Rx % Oligo or Azo

Stage 1 Stage 3 Testis Ca

Lymph Osteo Sarcoma

Sarcoma Leukemia

Which chemotherapeutic agents are

the worst for infertility?

Agent Spermato- Spermato- Spermatids Sertoli cells gonia cytes

Cisplatin +++ ++ + + Cyclophosphamide +++ Adriamycin +++ ++ + + Vinblastine +++ +++ +++

-100 0 100 200 300 0

50

100

150

200 The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. 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.

Hyperhaploid sperm

Days NOVP CHEMO

Genotoxicity: Sperm Aneuploidy with Chemotherapy

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

Hodgkins Disease FISH on chromos: X, Y, 8

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 Count Motility Morphology Birth Defects

Sulfasalazine Yes Yes Yes Possibly

Mesalamine No No No None

Azathioprine ?No ?No ?No 7.4% vs 4.4%

6-mercaptopurine

Moody et al. Int J Colorectal Dis. 12:220-4, 1997

Kjaergaard N et al. Scand J Gastroenterol 24:891-6, 1989

Dejaco C and Reinisch W. Gastroenterol 121:1048-1053, 2001

Norgard B et al. Aliment Pharmacol Ther 19: 679-85, 2004

• 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

II

Maintenance

Naive

How Toxic are “Milder Forms of Chemotherapy?

Mahadevan et al. Inflamm Bowel Dis.2005, 11: 395

Mahadevan et al. Inflamm Bowel Dis.2005, 11: 395

Infliximab and Semen Quality: Results Semen Quality Pre/Post Infusion: Maintenance (n=7)

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

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]

Unexposed N= 11 (range)

Exposed N=17 (range)

T-test 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 [>20 mln/ml]

71.8 (25.5,155) 65.7 (5.5,140) 0.71

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 [>40million]

102.1 (50, 141) 106.5 (8, 231) 0.83

Normal oval forms [>14%] 7.5% (1.5,12.5) 6.0 % (0,14) 0.37

Sample #2 Mean values

Unexposed N= 9 (range)

Exposed N=16 (range)

P value

DFI (%) 9.1% (3.9,14.7) 13.9% (3.7,31.6) 0.071

< 15% excellent >15 to <30% good >30% fair to poor

9 excellent 11 excellent 4 good 3 fair-poor

0.123

HDS [<15% = normal]

5.6% (4-8.7)

7.71% (3.1-22.9)

0.17

AZA/6MP Effects on Sperm DNA

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

Finasteride (1 or 5mg) Impaired spermatogenesis? HMG-CoA reductase inhibitors Alters cholesterol, ?infertility PDE5 inhibitors Altered motility?

Suspect Medications?

Name Effect

5-alpha Reductase Inhibitors and Male Infertility

Amory et al. JCEM. 2007, 92:1659

• 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)

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

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.

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

Dostal et al. Fundem Appl Toxicol 1996, 32: 285

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 Exposures

ETOH

Radiation

Tobacco

Heat

Pesticides Marijuana

Lead Cocaine

Stress

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

“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.

Lots of opinions…..

Copyright ©2006 American Physiological Society

Nindl, B. C. et al. J Appl Physiol 100: 120-128 2006; doi:10.1152/japplphysiol.01415.2004

Mean LH level over 12 hrs

• 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:

Effect of Extreme Physical Stress on LH and T

Physical: Continuous combat drills, marches Sleep: 2 x 1 hrs/day Caloric: 1 meal, 1 snack/day

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 sensitivity to LH with stress

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

BMI OR of infertility (CI)

<25.5 1 25-30 1.2 1.04-1.38 30-35 1.36 1.13-1.63

Nguyen et al. Hum Reprod.2007, 22: 2488

• Obese men have lower sperm counts and motilities. Utah cohort study of 526 infertile men. BMI <25 5.3% oligospermia BMI 25-30 9.2% oligospermia BMI >30 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)

4. Male factor infertility with azoospermia.

Mean=8mos

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: