BACKGROUND Semen quality is taken as a surrogate measure of male fecundity in clinical andrology, male fertility, reproductive toxicology, epidemiology and pregnancy risk assessments. Reference intervals for values of semen parameters from a fertile population could provide data from which prognosis of fertility or diagnosis of infertility can be extrapolated. METHODS Semen samples from over 4500 men in 14 countries on four continents were obtained from retrospective and prospective analyses on fertile men, men of unknown fertility status and men selected as normozoospermic. Men whose partners had a time-to-pregnancy (TTP) of < or =12 months were chosen as individuals to provide reference distributions for semen parameters. Distributions were also generated for a population assumed to represent the general population. RESULTS The following one-sided lower reference limits, the fifth centiles (with 95th percent confidence intervals), were generated from men whose partners had TTP < or = 12 months: semen volume, 1.5 ml (1.4-1.7); total sperm number, 39 million per ejaculate (33-46); sperm concentration, 15 million per ml (12-16); vitality, 58% live (55-63); progressive motility, 32% (31-34); total (progressive + non-progressive) motility, 40% (38-42); morphologically normal forms, 4.0% (3.0-4.0). Semen quality of the reference population was superior to that of the men from the general population and normozoospermic men. CONCLUSIONS The data represent sound reference distributions of semen characteristics of fertile men in a number of countries. They provide an appropriate tool in conjunction with clinical data to evaluate a patient's semen quality and prospects for fertility.

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World Health Organization reference values for human semen characteristics

WHO laboratory manual for the examination and processing of human semen

Infertility affects an estimated 15% of couples globally, amounting to 485 million couples Males are found to be solely responsible for 20-30% of infertility cases and contribute to 50% of cases overall However, this number does not accurately represent all regions of the world Indeed, on a global level, there is a lack of accurate statistics on rates of male infertility Our report examines major regions of the world and reports rates of male infertility based on data on female infertility Our search consisted of systematic reviews, meta-analyses, and population-based studies by searching the terms “epidemiology, male infertility, and prevalence” We identified 16 articles for detailed study We typically used the assumption that 50% of all cases of infertility are due to female factors alone, 20-30% are due to male factors alone, and the remaining 20-30% are due to a combination of male and female factors Therefore, in regions of the world where male factor or rates of male infertility were not reported, we used this assumption to calculate general rates of male factor infertility Our calculated data showed that the distribution of infertility due to male factor ranged from 20% to 70% and that the percentage of infertile men ranged from 2·5% to 12% Infertility rates were highest in Africa and Central/Eastern Europe Additionally, according to a variety of sources, rates of male infertility in North America, Australia, and Central and Eastern Europe varied from 4 5-6%, 9%, and 8-12%, respectively This study demonstrates a novel and unique way to calculate the distribution of male infertility around the world According to our results, at least 30 million men worldwide are infertile with the highest rates in Africa and Eastern Europe Results indicate further research is needed regarding etiology and treatment, reduce stigma & cultural barriers, and establish a more precise calculation

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A unique view on male infertility around the globe

The ability to control cell volume is pivotal for cell function. Cell volume perturbation elicits a wide array of signaling events, leading to protective (e.g., cytoskeletal rearrangement) and adap...

Physiology of cell volume regulation in vertebrates.

Oxidative stress occurs when the production of potentially destructive reactive oxygen species (ROS) exceeds the bodies own natural antioxidant defenses, resulting in cellular damage. Oxidative stress is a common pathology seen in approximately half of all infertile men. ROS, defined as including oxygen ions, free radicals and peroxides are generated by sperm and seminal leukocytes within semen and produce infertility by two key mechanisms. First, they damage the sperm membrane, decreasing sperm motility and its ability to fuse with the oocyte. Second, ROS can alter the sperm DNA, resulting in the passage of defective paternal DNA on to the conceptus. This review will provide an overview of oxidative biochemistry related to sperm health and will identify which men are most at risk of oxidative infertility. Finally, the review will outline methods available for diagnosing oxidative stress and the various treatments available.

/pdf/oxidative-stress-and-male-infertility-a-clinical-perspective-2nu3kdi0jn.pdf

Oxidative stress and male infertility—a clinical perspective

In a randomized, placebo-controlled, double-blind study we investigated whether high-dose oral treatment with vitamins C and E for 56 days was able to improve semen parameters of infertile men Ejaculate parameters included semen volume, sperm concentration and motility, and sperm count and viability Thirty-one patients without genital infection but with asthenozoospermia ( 7 x 10(6) spermatozoa/ml) (according to WHO criteria) were examined To investigate the influence of the epididymal storage period on semen parameters, the patients were asked to deliver two semen samples with abstinence times of 2 and 7 days both before and at the end of vitamin treatment After randomization, the patients received either 1000 mg vitamin C and 800 mg vitamin E (n = 15) or identical placebo capsules (n = 16) No changes in semen parameters were observed during treatment, and no pregnancies were initiated during the treatment period Combined high-dose antioxidative treatment with vitamins C and E did not improve conventional semen parameters or the 24-h sperm survival rate Prolonged abstinence time increased ejaculate volume (P < 005), sperm count (P < 005), sperm concentration (P < 005) and the total number of motile spermatozoa (P < 005)

/pdf/antioxidant-treatment-of-patients-with-asthenozoospermia-or-36c57f2np4.pdf

Antioxidant treatment of patients with asthenozoospermia or moderate oligoasthenozoospermia with high-dose vitamin C and vitamin E: a randomized, placebo-controlled, double-blind study

In certain cases of infertility in domestic species, and in the homozygous c-ros tyrosine kinase knockout mouse, males are infertile as a result of unopposed sperm swelling. This induces flagellar angulation, preventing their normal migration in the female tract. Angulation always occurs at the site of the cytoplasmic droplet located in mature sperm at the annulus (midpiece - principal piece junction). This article reviews the literature on the fate of the sperm's cytoplasmic droplet and suggests a role for it in volume regulation. A hypothesis is presented that during epididymal transit sperm acquire osmolytes accumulated by the epididymal epithelium. This is possibly driven by a mechanism of regulatory volume increase invoked by the hypertonicity of epididymal luminal fluid. These osmolytes are subsequently used for regulatory volume decrease after ejaculation into the relatively hypotonic female tract. Study of the mechanisms of sperm volume regulation may highlight new contraceptive leads.

Acquisition of volume regulatory response of sperm upon maturation in the epididymis and the role of the cytoplasmic droplet.

The interactions between spermatozoa and epididymal secretions are reviewed with respect to the nature of the interactions, the maturity of the spermatozoa and the environment in which spermatozoa mature. The estimated ionic strength of epididymal fluid is low enough for all peripheral proteins to be in close contact with the membrane. Two sorts of interactions are evident, those dependent on the state of the maturity of the spermatozoa (for example peripheral proteins and some integral proteins) and those independent of it (many integral proteins). For the former, a change in the sperm membrane charge must occur to permit recognition of peripheral proteins and the insertion of secreted charged integral membrane proteins may precede the interaction with more distally secreted products. For integral proteins, partition into the membrane may depend on the composition of the plasma membrane. Changes in the sterol content of particular domains have been documented and an array of lipid-binding proteins secreted by the epididymis may mediate these changes. The dependence of the transfer of lipid-anchored proteins to spermatozoa on membranous vesicles invites reassessment of the situation of spermatozoa within the epididymis and their contact with membranous vesicles and merocrine secretions that may be crucial to promoting physiological changes in spermatozoa.

Interactions between epididymal secretions and spermatozoa.

I. Maturation of Spermatozoa in the Epididymis.- 1. Acquisition in the Epididymis of Sperm Fertilising Ability.- 2. Involvement of the Epididymis in the Development of Sperm Fertilising Ability.- 3. The Nature of the Androgen-Dependent Epididymal Secretions Involved.- 4. Response of Immature Spermatozoa to Epididymal Secretions.- 5. Scope of this Review.- 6. Summary.- 7. References.- II. Fertilisation.- A. Sperm Motility.- 1. The Need for Flagellar Activity of Sperm for Them to Reach the Egg.- 2. The Ability of Immature Spermatozoa to Reach the Site of Fertilisation.- 3. Development in the Epididymis of Sperm Motility In-Vitro.- 4. The Nature of the Reduced Motility of Immature Spermatozoa.- 5. Involvement of the Epididymis in the Maturation of Motility.- 6. Induction of Motility in Immature Spermatozoa In-Vitro.- 7. Relationship of Induced Forward Motility to Fertilising Ability.- 8. Summary.- 9. References.- B. Capacitation.- 1. Detection of Capacitation.- 2. Changes in the Sperm Surface During Capacitation.- 3. Mechanisms of Capacitation.- 4. Consequences for Membrane Fluidity.- 5. Action of Decapacitation Factors.- 6. Maintenance of Motility.- 7. Requirements of Capacitation.- 8. Development in the Epididymis of the Ability of Spermatozoa to be Capacitated.- 9. Involvement of the Epididymis in Permitting Capacitation.- 10. Summary.- 11. References.- C. Consequences of Capacitation. I. Sperm-Egg Binding.- 1. Sperm-Egg Binding.- 2. Relationship to Capacitation.- 3. Relationship to the Acrosome Reaction.- 4. Mechanisms of Binding.- 5. Development in the Epididymis of the Ability of Sperm to Bind to Eggs.- 6. Involvement of the Epididymis in the Development of the Sperm Surface.- 7. Summary.- 8. References.- D. Consequences of Capacitation. II. The Acrosome Reaction.- 1. The Acrosome Reaction.- 2. Mechanism of the Acrosome Reaction.- 3. Requirements for the Acrosome Reaction.- 4. Stimulus to the Acrosome Reaction.- 5. Relationship to Capacitation.- 6. Relationship to Hyperactivated Motility.- 7. Relationship to Fertilisation.- 8. Site of the Acrosome Reaction.- 9. Consequences of the Acrosome Reaction.- 10. Development in the Epididymis of the Ability of Spermatozoa to Undergo the Acrosome Reaction.- 11. Involvement of the Epididymis in Permitting the Acrosome Reaction.- 12. Summary.- 13. References.- E. Consequences of Capacitation. III. Hyperactivation.- 1. Hyperactivation.- 2. Requirements of Hyperactivated Motility.- 3. Mechanisms of Hyperactivated Motility.- 4. Stimulus to Hyperactivated Motility.- 5. Relationship to Capacitation.- 6. Relationship to the Acrosome Reaction.- 7. Relationship to Fertilisation.- 8. Site of Hyperactivated Motility.- 9. Consequences of Hyperactivated Motility.- 10. Development in the Epididymis of the Ability of Sperm to Display Hyperactivated Motility.- 11. Involvement of the Epididymis in Permitting Hyperactivation.- 12. Summary.- 13. References.- F. Sperm-Egg Fusion.- 1. Binding to the Vitellus.- 2. Fusion with the Vitellus.- 3. Relationship to Capacitation.- 4. Relationship to the Acrosome Reaction.- 5. Relationship to Sperm Motility.- 6. Regions of the Sperm Head Involved in Fusion.- 7. Basis of Fusion.- 8. Development in the Epididymis of the Ability of Sperm to Fuse with Eggs.- 9. Involvement of the Epididymis in Permitting Sperm-Egg Fusion.- 10. Summary.- 11. References.- G. Post-Fusion Events.- 1. Activation of the Eggs.- 2. Decondensation of Sperm Chromatin.- 3. Formation of the Male Pronucleus.- 4. Chromosome Condensation.- 5. Development in the Epididymis of the Ability of Sperm to Interact with the Vitellus.- 6. Involvement of the Epididymis in Permitting Post-Fusion Events.- 7. Summary.- 8. References.- III. Function of the Epididymis and Its Secretory Products.- A. Epididymal Structure and Function.- 1. Introduction.- 2. Epididymal Structure.- 3. Blood Supply.- 4. Lymphatics.- 5. Methods of Study.- 6. Epithelial Cells.- 7. Testicular Control of Epididymal Function.- 8. Permeability of the Epididymal Epithelium.- 9. Resorptive Activity of the Epididymis.- 10. Secretory Activity of the Epididymis.- 11. Summary.- 12. References.- B. Secretion of Steroids by the Epididymis.- 1. Steroids in Epididymal Tissue.- 2. Origin of Epididymal Steroids.- 3. Testicular Control of Androgenic Function in the Epididymis.- 4. Endocrine Role of the Epididymis.- 5. Role of Steroids in Epididymal Function.- 6. Interactions of Steroids with Spermatozoa.- 7. Role of Steroids in Spermatozoal Function.- 8. Summary.- 9. References.- C. Resorption and Secretion of Ions by the Epididymis.- 1. Luminal Contents.- 2. Transporting Activities.- 3. Control of Transporting Activities.- 4. Role of Monovalent and Divalent Cations.- 5. Interactions of Ions with Maturing Spermatozoa.- 6. ATPase Activity in Spermatozoa.- 7. Polycations.- 8. Summary.- 9. References.- D. Epididymal Secretion of Glycerophosphocholine (GPC).- 1. Concentration in Epididymal Tissue.- 2. Origin of Epididymal GPC.- 3. Androgen Dependence.- 4. Role of GPC in Epididymal Function.- 5. Summary.- 6. References.- E. Epididymal Secretion of Carnitine.- 1. Concentration in Epididymal Tissue.- 2. Origin of Epididymal Carnitine.- 3. Androgen Dependence.- 4. Interaction of Carnitine with Maturing Spermatozoa.- 5. Roles of Carnitine in Epididymal Function.- 6. Summary.- 7. References.- F. Epididymal Secretion of myo-Inositol.- 1. Concentration in Epididymal Tissue.- 2. Origin of Epididymal Inositol.- 3. Androgen Dependence.- 4. Metabolism of Inositol.- 5. Interaction of Inositol with Maturing Spermatozoa.- 6. Role of Inositol in Epididymal Function.- 7. Summary.- 8. References.- G. Epididymal Secretion and Resorption of Proteins.- 1. Luminal Proteins.- 2. Origin of Epididymal Proteins.- 3. Protein Synthesis and Precursors in the Epididymis.- 4. Protein Secretion in the Epididymis.- 5. Androgen Dependence.- 6. Control of Protein Synthesis by Luminal Fluid.- 7. Site of Synthesis of Specific Proteins.- 8. Evidence for Interactions of Luminal Proteins with Spermatozoa.- 9. Binding of Proteins to Maturing Spermatozoa.- 10. The Nature of the Interaction.- 11. Site of Binding.- 12. Role of Proteins in Epididymal Function.- 13. Peptides.- 14. Resorption of Proteins by the Epididymis.- 15. Summary.- 16. References.- IV. Conclusions.- 1. The Importance of the Epididymis in Male Fertility.- 2. Summary.- Appendix I (Tables 1-21).- Appendix II (Figures 1-8).

Trevor G. Cooper

Papers

World Health Organization reference values for human semen characteristics

Antioxidant treatment of patients with asthenozoospermia or moderate oligoasthenozoospermia with high-dose vitamin C and vitamin E: a randomized, placebo-controlled, double-blind study

Acquisition of volume regulatory response of sperm upon maturation in the epididymis and the role of the cytoplasmic droplet.

Interactions between epididymal secretions and spermatozoa.

The Epididymis, Sperm Maturation and Fertilisation