Molecular and other predictors for infertility in patients with varicoceles
Susan Benoff1,2,3,5, Joel L. Marmar4, Ian R. Hurley1
1
Fertility Research Laboratories, Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, 2Department of Obstetrics and Gynecology, North Shore University Hospital, Manhasset, New York, 3Departments of Obstetrics and Gynecology and Cell Biology, New York University School of Medicine, New York, New York, 4Department of Urology, Robert Wood Johnson School of Medicine, Camden, New Jersey, 5350 Community Drive, Room 125, Manhasset, New York 11030
TABLE OF CONTENTS
- 1. Abstract
- 2. Definition
- 3. Frequency of occurrence and presentation
- 3.1. Association with infertility and current treatment
- 4. The varicocele controversy
- 5. Potential mechanisms
- 6. Deficits already identified
- 6.1. Scrotal/testicular hyperthermia
- 6.2. Increased venous pressures
- 6.3. Accumulation of toxic substances
- 6.3.1. Intrinsic toxins
- 6.3.2. Extrinsic toxins
- 6.4. Hypoxia
- 6.5. Hormonal imbalance
- 6.6. Additional molecular changes
- 7. Use of animal models
- 7.1. Experimental left varicocele
- 7.1.1. Recapitulation of effects observed in human males with varicoceles
- 7.1.2. Additional changes not yet reported in human subjects
- 7.2. Elevated temperature
- 7.3. Effect of toxins
- 7.3.1. A potential role for genetics in sensitivity or resistance to cadmium-induced testicular damage
- 7.4. Androgen deprivation
- 8. Medical therapies
- 8.1. Oxidative stress
- 8.1.1. Antioxidants
- 8.1.2. Supplementary zinc
- 8.1.3. Anti-inflammatory drugs
- 8.2. Hormones
- 8.3. Toxic substance antagonists
- 9. Predictor variables
- 9.1. Semen parameters
- 9.2. Testis volume and histology
- 9.3. Scrotal/testicular hyperthermia
- 9.4. Toxic substances
- 9.5. Factors related to hypoxia
- 9.6. Hormones
- 9.7. Other prognostic factors
- 10. Future directions
- 10.1. Etiology of varicose veins
- 10.2. Points for investigation in infertile men with varicoceles
- 10.2.1. Smooth muscle cell proliferation
- 10.2.2. VEGF
- 10.2.3. TGF-beta-1
- 10.2.4. Angiotensin
- 10.2.5. Fibroblast growth factors
- 10.2.6. Matix metalloproteases
- 10.2.7. Other possiblities
- 11. Concluding comments
- 12. Acknowledgements
- 13. References
1. ABSTRACT
Varicoceles are a treatable cause of male infertility, but very clinically diverse. Both histologic and molecular changes occur in the testes of men with varicocele. Physical measurements (scrotal temperature, testicular volume, pressure within the pampiniform plexus, basal lamina thickness) correlate with prognosis, but these correlations have not been accepted as predictors of successful repair because of variation within patient populations. Conventional semen parameters similarly correlate, but these correlations apply only to men with >5 x106 sperm/ejaculate. Levels of toxicants (e.g. norepinephrine, cadmium), reactive oxygen species byproducts, and hormones, their receptors and modulators have been evaluated as predictors in small-scale studies. Medical therapies (antoxidants, anti-inflammatories and hormones) have been applied empirically to small groups of patients with positive results that have not been verified in large-scale trials. Thus, urologists still face a challenge to determine which patients will benefit from varicocelectomies and/or medical interventions. In this review we summarize our current understanding of the pathophysiology of varicoceles, and discuss some of the new findings that may be applicable to specific clinical situations.
