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Male Fertility Overview
 

Male Fertility Overview

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Mark Perloe, M.D., Medical Director, Georgia Reproductive Specialists review Male Fertility. Visit www.IVF.com for more information.

Mark Perloe, M.D., Medical Director, Georgia Reproductive Specialists review Male Fertility. Visit www.IVF.com for more information.

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  • It is not a 50/50 chance as to choosing the correct oviduct for a sperm. Sperm have a tropism for ova of their species—they are attracted toward the ovum in the correct oviduct, making species-specific fertilization and fertilization in general more likely.
  • Passage of sperm: Since sperm can only move 2 to 3 mm per minute using their own power, they must be helped along somehow. At the shortest, sperms can be found in the oviducts only 5 minutes after ejaculation. Other sperms can take 45 minutes. The Natural Family Planning method of attempting pregnancy relies on changes in mucus thickness for the timing of intercourse—the character of the mucus is a good indicator of the presence of a viable egg.
  • For a test to be useful, it must have a threshold above and below which it will provide discriminatory and predictive capabilities, with little overlap between fertile and infertile men. Conventional semen parameters often do not meet these standards. Although widely used thresholds for normal semen measurements have been published by the World Health Organization (WHO), [World Health Organization. WHO laboratory manual for the examination of human semen and semen-cervical mucus interaction. Singapore: Press Concern, 1980; Idem. WHO laboratory manual for the examination of human semen and semen-cervical mucus interaction. 2nd ed. Cambridge, England: Cambridge University Press, 1987; Idem. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 3rd ed. Cambridge, England: Cambridge University Press, 1992; Idem. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 4th ed. Cambridge, England: Cambridge University Press, 1999.] the available norms for sperm concentration, motility, and morphology fail to meet rigorous clinical, technical, and statistical standards. In recognition of these limitations, the nomenclature in the most recent WHO manual (1999) for semen evaluation was changed from “normal” to “reference” values. Recent prospective studies of semen quality and fertility concluded that the current WHO reference values should be reconsidered.
  • For a test to be useful, it must have a threshold above and below which it will provide discriminatory and predictive capabilities, with little overlap between fertile and infertile men. Conventional semen parameters often do not meet these standards. Although widely used thresholds for normal semen measurements have been published by the World Health Organization (WHO), [World Health Organization. WHO laboratory manual for the examination of human semen and semen-cervical mucus interaction. Singapore: Press Concern, 1980; Idem. WHO laboratory manual for the examination of human semen and semen-cervical mucus interaction. 2nd ed. Cambridge, England: Cambridge University Press, 1987; Idem. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 3rd ed. Cambridge, England: Cambridge University Press, 1992; Idem. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 4th ed. Cambridge, England: Cambridge University Press, 1999.] the available norms for sperm concentration, motility, and morphology fail to meet rigorous clinical, technical, and statistical standards. In recognition of these limitations, the nomenclature in the most recent WHO manual (1999) for semen evaluation was changed from “normal” to “reference” values. Recent prospective studies of semen quality and fertility concluded that the current WHO reference values should be reconsidered.
  • Suggests that the coefficient of variation, repeatability and statistical soundness of measures of conventional semen parameters and sperm function tests are weak. Measures of DNA fragmentation independent of standard semen measures and clearly show that motile, morphologically normal sperm may have extensive DNA fragmentation. Spermatozoa with defective DNA can fertilize an oocyte, produce high quality early stage embryos and then, in relationship to extent of DNA damage, fail in producing a successful term pregnancy. The 23 chromosomes in the sperm head are made up of chromatin, which consists of DNA and proteins. DNA packing during the transition of histone to protomine complex at spermiogenesis (late spermatid stage) Apoptosis is a major regulatory mechanism during normal spermiogenesis. Findings suggest that there may be an abortive apoptotic process which extends until late stage of spermatogenesis resulting in fragmented DNA. 3. ROS cause peroxidative damage to the perm plasma membrane and attack DNA, inducing strand breaks and other oxidative-induced DNA damage
  • Suggests that the coefficient of variation, repeatability and statistical soundness of measures of conventional semen parameters and sperm function tests are weak. Measures of DNA fragmentation independent of standard semen measures and clearly show that motile, morphologically normal sperm may have extensive DNA fragmentation. Spermatozoa with defective DNA can fertilize an oocyte, produce high quality early stage embryos and then, in relationship to extent of DNA damage, fail in producing a successful term pregnancy. The 23 chromosomes in the sperm head are made up of chromatin, which consists of DNA and proteins. DNA packing during the transition of histone to protomine complex at spermiogenesis (late spermatid stage) Apoptosis is a major regulatory mechanism during normal spermiogenesis. Findings suggest that there may be an abortive apoptotic process which extends until late stage of spermatogenesis resulting in fragmented DNA. 3. ROS cause peroxidative damage to the perm plasma membrane and attack DNA, inducing strand breaks and other oxidative-induced DNA damage

Male Fertility Overview Male Fertility Overview Presentation Transcript

  •  
  • Anatomy
  • Gametogenesis Control
    • Hypothalamus
    Anterior Pituitary Sertoli Cells GnRH FSH LH Leydig Cells SCF/Inhibin Testosterone Spermatogenesis
  • S permatogenesis ( sperm = seed; genesis = to produce)
    • 1) SPERMATAGONIA
      • Stem cell renewal and progression into meiosis.
    • 2) SPERMATOCYTES
      • One diploid cell becomes 4 haploid cells ( meiosis )
    • 3) SPERMATIDS
      • Diploid cells differentiate & mature ( spermiogenesis)
    • 4) SPERM (Spermatazoa)
      • Spermatid dissengages excess cytoplasm
      • Released into the lumen of the seminiferous tubule ( spermiation ).
  • Testicular Anatomy
  • A - Seminiferous tubules contain germ cells & Sertoli cells B – Leydig cells produce testosterone in response to LH C – Tubal Lumen
  • Sertoli Cells
    • specialized cells that regulate sperm development
    • secrete nourishment, androgen binding protein (ADP) and inhibin
    • form the blood-testes barrier
    • phagocytize excess sperm cytoplasm
    • produce fluid for sperm transport
  •  
  • Spermatogenesis
    • Duration 70 – 80 days
    • Production / day 20 – 375 x 10 6
    • Sperm concentration (/ ml semen)
      • Mean 100 x 10 6
      • Range 40 – 250 x 10 6
      • Infertility < 20 x 10 6
    • Epididymal transit time 6 days
  • Sperm and Fertilization
    • must reach and penetrate the ovum.
    • must activate the ovum to resume nuclear and cytoplasmic division necessary for embryonic development.
    • contributes the paternal complement of chromosomes to the new embryo.
    • determines the sex of the embryo.
  • Sperm Trivia
    • Approximately 250 to 600 MILLION sperms are deposited at cervical opening during ejaculation, enough sperm to fertilize every woman in the US
    • Only about 200 sperms reach the fertilization site; most degenerate and are absorbed by the female genital tract.
    • The average swimming speed of a sperm is 8 inches per hour
    • Some sperm are held up by the folds of the cervix and are gradually released into the cervical canal; this gradual release increases the chances of fertilization.
    • Most human sperms do not survive longer than 48 hours in the female genital tract.
  • Accessory Sex Organs
    • Seminiferous tubules
      • Spermatogenesis
    • Rete testis
      • Testosterone absorption
    • Efferent ducts
      • Spermatid transport
    • Epididymis
      • Spermatid maturation
      • Sperm storage
    • Seminal vesicles
      • Fluid for conveyance
      • Nutrients
    • Prostate
      • Fluid
      • Acid Phosphotase
    • Bulbourethral glands
      • Neutralize pH
      • Supplies nutrients
  • Male Fertility Factors Determinants of Male Fertility
    • Adequate spermatogenesis
    • Adequate anatomy/semen parameters
    • Adequate sperm delivery
  • Are Sperm Counts Declining
    • General decline in semen quality
      • Decreased count ~2%, motility ~0.6% per yr
    • Men produce 50% less sperm than 50 years ago.
        • Jarkko Pajarinen Helsinki University 1997
    • Geographical variation in this decline suggests not only an environmental cause, but also ‘an environmental impact’
  • The Sperm Head Head: EM, LS × 14 000 AC = acrosome; PM = plasma membrane From Wheater’s Functional Histology, 4 th ed., 2000. The head of a mature sperm, lengthwise, is approximately 1/20 the diameter of a mature ovum.
  • The Sperm Neck Neck (middle piece and principal piece): EM, LS × 17 000 Mi = mitrochondria; C = cytoplasm; F, Rn, Rb, & An = all parts of flagellum structure From Wheater’s Functional Histology, 4 th ed., 2000.
  • Sperm Tail
  • Sperm GPS or… How do they know where to go?
    • During ejaculation, the sperm are propelled from the urethra by peristaltic contractions of the vas deferens musculature.
    • Sperm use their flagellum to move through the cervical canal.
    • The enzyme vesiculase (from seminal vesicles) coagulates some of the semen to prevent backflow into the vagina.
    • Fructose (from seminal vesicles) is an energy source for the sperm.
    • At ovulation, the cervical mucus increases in amount and becomes less thick, allowing easier sperm transport.
    • Passage of the sperm through the uterus and oviduct occurs mainly due to muscular contractions of these organs.
    Sperm GPS or… How do they know where to go?
  • Capacitation: readying the sperm
    • Sperm cannot fertilize oocytes when they are newly ejaculated.
    • The process of capacitation takes 5-7 hours.
    • Capacitated sperms are more active.
    • Location: capacitation occurs in the uterus and oviducts and is facilitated by substances of the female genital tract.
    • The acrosomal reaction cannot occur until capacitation has occurred.
  • Sperm and Egg A match made in heaven!
    • Capacitation
    • Acrosome reaction
    • Passage through corona radiata
    • Zona Pellucida penetration
    • Zona reaction
    • Fusion of sperm & egg plasma membranes
    • 2 nd meiotic division of oocyte is completed
    • Formation of male and female pronuclei
  • Infertility Primary infertility is the inability to conceive a pregnancy, after one year of unprotected intercourse. Secondary infertility describes couples who previously conceived at least once, but have achieved another pregnancy
  • Estrogen-like industrial chemicals in water
  • Male Fertility Factors Defects in Spermatogenesis
    • Stress
    • Age
    • Toxins
      • Lead, DBCP, EDB, TCE, 2-ME, 2-EE, Dioxin
      • Plastics, diesel fuel, tobacco, alcohol, cannabis
    • Exposure to radiation of chemotherapy
    • Endocrine dysfunction
      • Acquired: prolactinoma
      • Congenital: Kallman syndrome
    • Genetic abnormalities
    • Cryptorchidism
    • Infections
      • Mumps orchitis, chickenpox
      • STI: Chlamydia, gonorrhea, syphilis
    • Varicocele
    Male Fertility Factors Defects in Spermatogenesis
  • From: Netter, F.H., The CIBA Collection Varicocele Defects in spermatogenesis
  • 39% of infertile men have a varicocele Varicocele
    • Activities
      • Hot tub, sauna, hot baths, long-distance running, bicycle riding, truck drivers
      • Tight underwear
    • Seasonal variation
      • Men with lower sperm counts exhibited the greatest seasonal effects
      • Texas summer
        • Sperm conc  32%
        • Sperm count  28%
        • % Motile  28%
    Heat Defects in spermatogenesis
  • Paternal Occupation
    • Several studies compare paternal occupational exposures with adverse reproductive outcomes
      • Spontaneous abortion
      • Developmental disorders
      • Childhood cancer
    • Anesthetist 25%  congenital anomalies
    • Nuclear workers 6.4 OR for childhood leukemia or NHL
    • Mechanisms are often uncertain
      • Linking exposure with time of conception can be crucial since expression (~70 d) may be brief
    • Coital Factors:
      • Erectile dysfunction
      • Ejaculatory incompetence
      • Hypospadias
      • Premature ejaculation
      • Use of spermicidal lubricants
    Male Fertility Factors Inadequate Sperm Delivery
  • Male Fertility Factors Inadequate Sperm Delivery
    • Retrograde ejaculation
      • Postsurgical (RPND)
      • Beta blockers
      • Diabetic neuropathy
  • Male Fertility Factors Clinical Evaluation
    • Medical History:
    • Physical examination
    • Semen analysis (round cell stain)
    • SCSA/SDFA, SDD, P34
    • Endocrine profile: Free T, FSH, PRL, Estradiol, LH?
    • Other tests
      • Sperm Ab, Sperm penetration, HOST, Sperm chromosome analysis, Acrosin test, PCT
  • CONSECUTIVE SEMEN DONOR CONCENTRATIONS OVER FOUR YEARS Sperm Count Variability
  • Sperm Morphology
  • Round Cell Stain
    • Fertility rate begins to decline at higher levels than the WHO parameters.
      • Slama (2002) 942 spontaneously pregnant couples (20-45 yrs.)
      • threshold values above or below which the variations of a semen parameter associated with time to pregnancy ceased to have an effect on time to pregnancy.
      • The threshold value for sperm concentration was 55 x 10 6 /ml and for total sperm count was 145 x 10 6 sperm.
    Semen Analysis Criticism
      • Slama R, Eustache F, Ducot B, Jensen TK, Jørgensen N, Horte A, Irvine S, Suominen J, Andersen AG, Auger J, Vierula M, Toppari J, Andersen AN, Keiding N, Skakkebæk NE, Spira A, Jouannet P. Time to pregnancy and semen parameters: a cross-sectional study among fertile couples from four European cities. Hum. Reprod. 2002; 17:503-515. (European)
      • Zinaman (2000) 12-month trial of 200 couples (ages 20 – 51 yrs.)
      • Value of semen quality measures for predicting human male fertility potential
      • Lower pregnancy rates below 30 x 10 6 sperm/ml and 80 x 10 6 total number of sperm, representing 50% and 100% higher values for concentration and count, respectively, than the WHO lower limit standard of normal.
        • Zinaman MJ, Brown CC, Selevan SG, Clegg ED. Semen quality and human fertility: a prospective study with health couples. J Androl 2000; 21:145-53. (United States)
    Semen Analysis Criticism
      • Bonde (1998) 430 couples (ages 20 – 35 yrs.) for 6 months with no prior reproductive experience.
      • Probability of conception within 6 months was directly related to the sperm concentration
      • Statistically lower conception rates (51.2% vs. 65%) at a “cut-off” sperm concentration less than 40 x 10 6 /ml, twice the lower limit of the WHO standard.
    Semen Analysis Criticism
        • Bonde JPE, Ernst E, Jensen TK, Hjollund NHI, Kolstad H, Henriksen TB, Scheike T, Giwercman A, Olsen J, Skakkabaek NE. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet 1998; 352:1172-7. (Danish)
      • Guzick (2001) evaluated two semen specimens from 765 infertile couples and 696 fertile couples.
        • Fertility : > 48.0 x 10 6 /ml, > 63%, and > 12%, respectively;
        • Subfertility : < 13.5 x 10 6 /ml, < 32%, and < 9%, respectively.
      • The odds of conception decrease when values are less than those associated with fertility.
    Semen Analysis Criticism
        • Guzick DS, Overstreet JW, Factor-Litvak P, Brazil CK, Nakajima ST, Coutifaris C, Carson SA, Cisneros P, Steinkampf MP, Hill JA, Xu D, Vogel DL, For the National Cooperative Reproductive Medicine Network. Sperm morphology, motility, and concentration in fertile and infertile men. NEJM 2001;345(19):1388-1393.
    • Background:
      • Sperm chromatin is a highly organized compact structure consistising of DNA and heterogeneous nucleoproteins.
      • Sperm DNA damage may occur by at least 3 punitive mechanisms:
        • Defective chromatin condensation during spermiogenesis
        • Initiation of apoptosis during spermatogenesis or transport of sperm through male or female genital tract
        • Oxidative stress mainly resulting from reactive oxygen species produced internally and externally.
    DNA Fragmentation
  • Sperm Chromatin Structure AssaySCSA SCSA/SDFA test is a good predictor, relative to other sperm measures, for the clinical diagnosis of male infertility
      • Sperm are stained according to their level of DNA fragmentation.
      • The DNA Fragmentation Index (DFI) has been developed using SCSA/SDFA test data and is expressed as the percentage of sperm in a sample with elevated levels of DNA fragmentation.
      • Miscarriage rate is doubled
      • Levels > 30% DFI predict a reduced fertility potential
    SCSA/SDFA
  • DNA Fragmentation Study Results
    • 998 cycles from 637 patients
    • Unexplained infertility, with sufficient sperm count did IUI
    • Female factor infertility did IVF
    • <500,000 sperm after gradient did ICSI
    Bungum, Human Reprod , 2007
  • Infertility Treatment Abnormal DNA Fragmentation
    • Repair varicocele
    • Treat infection
    • NSAID’s
    • Antioxidants
      • Vit C, Vit E, Juice Plus, Selenium
    • Zinc supplementation
    • Stop smoking
    • Avoid hot baths, jacuzzi
    • IVF with ICSI
  • SDD Sperm DNA Decondensation Assay
    • Study A
      • Retrospective study of 58 patients receiving IUI or IVF (w/o ICSI)
        • None with abnormal SDD had live birth
        • Those with normal SDD had a 28% success rate
    • Study B
      • Prospective ICSI only study..50 patients
        • 20 with abnormal SDD
        • 30 with normal SDD
      • ICSI success rates were not statistically different
    Leader, et al: Sperm DNA Decondensation Assay and Selection of Assisted Reproductive Technology Method, ASRM 2007
  • Y Microdeletion Testing
  • Sperm Chromosome Testing
    • Ejaculatory disorders
      • Sympathomimetic drugs: 20-30%
    • Retrograde ejaculation
      • Sperm rescue from urine: variable success rate
    • Antisperm antibody
      • Immunosuppressive drugs: variable success
    • Hypothalamic Hypogonadism
      • Clomiphene, hCG, injectable gonadotropins
    • L-Carnitine/Acetyl L-carnitine
    Medical Treatment Outcomes
  • L-carnitine and Acetyl-L-carnitine Human Research Findings
      • Improved Motility
        • Observed in idiopathic astheno- or oligoasthenozoospermia
        • Increased % motile sperm – mean change of 35.3 to 99.6% (Campaniello, 1989; Costa, 1994; Loumbakis, 1995; and Vitali, 1995)
        • Increased % rapid linear progression (RLP) - mean change of 54.5 to 180% (Costa, 1994; Micic, 1998; Vitali, 1995)
        • CASA - increased mean velocity, linearity index and maximum amplitude (Costa, 1994)
        • Significant improvement even among poorest motility (RLP < 5%) - (Costa, 1994)
  • L-carnitine and Acetyl-L-carnitine Human Research Findings
  • L-carnitine and Acetyl-L-carnitine Human Research Findings
      • Sperm Concentration and Total Count
        • Increased sperm concentration:
          • Asthenozoospermic subjects – 7.7 to 78.8% mean change - (Costa, 1994; Muller-Tyl, 1988; and Vitali, 1995)
          • Oligoasthenozoospermic subjects – 44.9 to 209% mean change- ( Micic, 1998; and, Moncada, 1992)
        • Increased total sperm count – 14.7% mean change - (Costa, 1994)
  • L-carnitine and Acetyl-L-carnitine Human Research Findings
  • Placebo-controlled randomized double-blind trial of Proxeed in men with asthenozoospermia
    • 30 men and 26 controls with concentration 10-40 m/cc, forward motility <15% and total motility 10-40%
    • Baseline, 3 mos., 6 mos. of Proxeed therapy
    • Increased in post-treatment total motile sperm per ejaculate 30.6 vs 24.1 million. (p=0.042)
    • Increased forward motile sperm per ejaculate 25.1vs. 19.9 (p=0.044)
    • Effect of treatment greatest with lowest T 0 values
    • No change in volume, count, or morphology
    • Four spontaneous pregnancies in treatment group
      • 2@4mos, 5mos & 6mos.
      • All had higher T 0 forward motile sperm per ejaculate & showed no significant improvement
      • Lenzi A, et. Al. Fertil Steril 2004 June;81(6):1578-1584
      • Oxygen Free Radical Production
        • Reduced ROS production
        • Recent work and small numbers
        • Clinical problems examined - s/p epididymitis (bacterial and non-bacterial) and varicocele repair
        • Increased motility
        • Improved morphology
        • Improved IVF results (% fertilized and pregnancies) Vicari, 1997; Vicari, Cerri, et al., 1999, Vicari, Cataldo, et al., 1999
    L-carnitine and Acetyl-L-carnitine Human Research Findings
      • ALC effect on ROS production and IVF program outcome
        • Post treatment IVF results
          • ALC group 66.1% oocyte fertilization and 2 preg.
          • Vit. E group 24.5% oocyte fertilization and no preg.
          • Control 8.6% oocyte fertilization and no preg
          • Vicari, E. 1997
    L-carnitine and Acetyl-L-carnitine Human Research Findings
  • L-carnitine and Acetyl-L-carnitine Human Research Findings
  • Surgical Treatment Outcomes
    • Varicocele repair
      • Probability of semen improvement: 50-70%
      • Probability of pregnancy: 25-50%
    • Vasoepididymostomy
      • Patency rates: 60-70%
      • Probability of pregnancy: >30%
    • Vasovasostomy
      • Overall pregnancy rate: 50-60%
  • IUI vs IVF
    • Effect of the total motile sperm count on the efficacy and cost-effectiveness of intrauterine insemination and in vitro fertilization
      • Female age, gravidity, and use of ovulation predict pregnancy after IUI
      • With total motile sperm count < 10 million, IVF with ICSI was more cost-effective than IUI
      • Van Voorhis BJ Fertil Steril 2001 Apr;75(4):661-8
  • Male Infertility IUI Effectiveness
    • With a concentration of less than five million per milliliter, the per-cycle pregnancy rate was 2.5 percent. When initial values are lower, IUI has little chance of success.
    • With a count of less than 10 million, the per-cycle pregnancy rate was one percent.
    • When motility was less than 20 percent, the per-cycle pregnancy rate was 1.2 percent
    • When normal morphology was less than five percent, no pregnancies occurred.
    • With a total motile count of less than five million, the per-cycle pregnancy rate was 2.3 percent.
    • Dickey RP, et al: Fertil Steril 1999 Apr;71(4):684-9
  • ICSI I ntra- C ytoplasmic S perm I njection
  • ICSI Issues
    • Success primarily dependent on maternal age
    • Obstructive vs. non-obstructive azozoospermia
    • SCSA testing
    • Sperm optimization
      • Proxeed, Zn, Selenium, NSAID, antibiotic, antioxidants
    • Chromosomal analysis & Y microdeletion testing
    • Source of sperm
      • Ejaculate
      • Testicular biopsy vs. aspirate
      • Fresh vs. cryopreserved
    • ? Risk of fetal anomalies
  • For more information:
    • Georgia Reproductive Specialists
        • www.ivf.com
    • INCIID
        • www.inciid.org
    • Repromedix
        • www.repromedix.com
    • SCSA Diagnostics
        • www.scsadiagnostics.com
    • Sigma Tau
      • www.ivf.com/proxeed.html