Male Fertility Overview

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)


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)


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.


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)


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


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)


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


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



Efficacy of L-carnitineMean (±SEM) Total Sperm CountCosta M et al, Andrologia 1994; 26(3):155-159

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Length of Treatment (*p<0.001)

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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

http://www.ivf.com/

http://www.inciid.org/

http://www.repromedix.com/

http://www.scsadiagnostics.com/

http://www.ivf.com/proxeed.html

Male Fertility Overview

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