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Mark Perloe, M.D., Medical Director, Georgia Reproductive Specialists review Male Fertility. Visit www.IVF.com for more information.
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MARK PERLOE, M.D. GEORGIA REPRODUCTIVE SPECIALISTS
MALE FACTOR INFERTILITY
Anatomy
Gametogenesis Control
Hypothalamus
Anterior Pituitary
Sertoli Cells
GnRH
FSH LH
Leydig CellsSCF/Inhibin Testosterone
Spermatogenesis
Spermatogenesis (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 inresponse 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 106
Sperm concentration (/ ml semen) Mean 100 x 106
Range 40 – 250 x 106
Infertility < 20 x 106
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 000AC = acrosome; PM = plasma membraneFrom Wheater’s Functional Histology, 4th 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 000Mi = mitrochondria; C = cytoplasm; F, Rn, Rb, & An = all parts of flagellum structureFrom Wheater’s Functional Histology, 4th 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 2nd 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
Male25%
Anovluation16%
Cervical3%Tubal
20%
Uterine2%
Multiple25%
Unknown9%
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
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CONSECUTIVE SEMEN DONORCONCENTRATIONS 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 106/ml and for total sperm count was 145 x 106 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 106 sperm/ml and 80 x 106 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 106/ml, twice the lower limit of the WHO standard.
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)
Semen Analysis Criticism
Guzick (2001) evaluated two semen specimens from 765 infertile couples and 696 fertile couples.
Fertility: > 48.0 x 106/ml, > 63%, and > 12%, respectively;
Subfertility: < 13.5 x 106/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:1. Defective chromatin condensation during
spermiogenesis2. Initiation of apoptosis during spermatogenesis or
transport of sperm through male or female genital tract
3. 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
Effect on Sperm % Motility
Author N Pre (%) Post(%) Increase p Asthenospermia Campaniello, 1988 9 25 47 88.0% <0.01 Costa, 1994 100 26.9 36.4 35.3% <0.001 Loumbakis, 1995 20 24.7 42.8 73.3% <0.01 Vitali, 1995 47 26.8 53.5 99.6% N.R. Lenzi 2004 30 23.2 31.1 34.1% N.S. Oligoasthenospermia Moncada, 1992 20 21.7 38.2 76.9% <0.003
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
Effect on Sperm Concentration
Author N Pre* Post* Chg. p astheno- Costa, 1994 100 49.4 53.2 8% <0.001 astheno- Muller-Tyl, 1988 30 45.0 65.0 46% N.R. astheno- Vitali, 1995 47 88.9 159.0 79% N.R. severe oligo- Micic, 1998 20 1.3 3.9 209% <0.014 mild oligo Micic, 1998 20 13.7 22.9 67% <0.007 oligoastheno Moncada, 1992 20 9.8 14.2 45% N.S. mild oligo Lenzi, 2004 30 18.1 22.1 22% N.S. * mean ( x 106/ml) N.R. – not reported N.S. – not statistically significant
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 T0 values No change in volume, count, or morphology Four spontaneous pregnancies in treatment group
2@4mos, 5mos & 6mos. All had higher T0 forward motile sperm per ejaculate &
showed no significant improvementLenzi 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
Efficacy of L-carnitineMean (±SEM) Total Sperm CountCosta M et al, Andrologia 1994; 26(3):155-159
100110120130140150160170180190200
Initial 2 mo.* 4 mo.* 2 mo.Post*
Length of Treatment (*p<0.001)
To
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per
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Efficacy of L-carnitineMean (±SEM) % Motile Sperm
Costa M et al, Andrologia 1994; 26(3):155-159
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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 Intra-Cytoplasmic Sperm Injection
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 SpecialistsGeorgia Reproductive Specialists www.ivf.com
• INCIIDINCIID www.inciid.org
• RepromedixRepromedixwww.repromedix.com
• SCSA DiagnosticsSCSA Diagnostics www.scsadiagnostics.com
• Sigma TauSigma Tau www.ivf.com/proxeed.html