Genetics and Infertility

BySalwa Hassan Teama

M.D. N.C.I .Cairo University, Egypt

ContentsContents InfertilityInfertility Causes of Male infertilityCauses of Male infertility Male Partner Diagnostic TestsMale Partner Diagnostic Tests Semen AnalysisSemen Analysis Female Partner Diagnostic TestsFemale Partner Diagnostic Tests Normal karyotypeNormal karyotype Genetic Tests of InfertilityGenetic Tests of Infertility IVFIVF

InfertilityInfertility

Definition; "failure to conceive following one year Definition; "failure to conceive following one year of unprotected sexual intercourse." For young of unprotected sexual intercourse." For young and healthy heterosexual couples having and healthy heterosexual couples having frequent intercourse, about 85% will be frequent intercourse, about 85% will be pregnant after one year of trying and about pregnant after one year of trying and about 93% will be pregnant after two years of trying to 93% will be pregnant after two years of trying to

conceiveconceive..

InfertilityInfertility : :Timely Timely EvaluationsEvaluations

Initial infertility evaluations should be Initial infertility evaluations should be individualized, taking into consideration the individualized, taking into consideration the medical history of the couple and the age of the medical history of the couple and the age of the

female partnerfemale partner . .

Helping you build your Helping you build your familyfamily

True infertilityTrue infertility only occurs in a few specific situationsonly occurs in a few specific situations : : Women with blocked fallopian tubes.Women with blocked fallopian tubes. Women that has no uterus or no egg follicles Women that has no uterus or no egg follicles

(menopause or premature ovarian failure). (menopause or premature ovarian failure). Men who have no sperm. Men who have no sperm.

In these situations, successful conception will only occur with the In these situations, successful conception will only occur with the

use of specific medical technology, sometimes the use of a third use of specific medical technology, sometimes the use of a third party is necessary to provide eggs, sperm or a uterus to carry the party is necessary to provide eggs, sperm or a uterus to carry the

pregnancypregnancy..

InfertilityInfertility

SubSub-- Fertility Fertility

Any other diagnoses in couples, besides the Any other diagnoses in couples, besides the mentioned…, consider some degree of sub-fertility. mentioned…, consider some degree of sub-fertility. That is, there is some chance, even small of That is, there is some chance, even small of conception without the assistance of fertility conception without the assistance of fertility

treatmentstreatments . .

The role of the fertility specialist is to guide the patient The role of the fertility specialist is to guide the patient towards timely evaluations and treatment decisions towards timely evaluations and treatment decisions that will significantly improve their chances of that will significantly improve their chances of

becoming parentsbecoming parents . .

Causes of Male infertilityCauses of Male infertility

The primary causes of The primary causes of male infertility aremale infertility are:: Impaired sperm production, Impaired sperm production, Impaired sperm delivery, and Impaired sperm delivery, and Testosterone deficiency (hypogonadism).Testosterone deficiency (hypogonadism). Infertility can result from a condition that is present at Infertility can result from a condition that is present at

birth (congenital) or that develops later (acquired)birth (congenital) or that develops later (acquired)..

Causes of male infertilityCauses of male infertility

Chemotherapy Chemotherapy Defect or obstruction in the reproductive system such Defect or obstruction in the reproductive system such

as failure of testes to descend into the scrotum as failure of testes to descend into the scrotum (cryptorchidism) or absence of one or both testicles (cryptorchidism) or absence of one or both testicles (anorchism). (anorchism).

Disease (e.g., cystic fibrosis, sickle cell anemia, Disease (e.g., cystic fibrosis, sickle cell anemia, sexually transmitted diseases [STDs]).sexually transmitted diseases [STDs]).

Causes of male infertilityCauses of male infertility

Hormone dysfunction (testosterone deficiency; caused by a Hormone dysfunction (testosterone deficiency; caused by a disorder in the hypothalamic-pituitary-gonadal axis). disorder in the hypothalamic-pituitary-gonadal axis).

Infection (e.g., prostatitis, epididymitis, orchitis; can cause Infection (e.g., prostatitis, epididymitis, orchitis; can cause irreversible infertility if occur before puberty). irreversible infertility if occur before puberty).

Injury (e.g., testicular trauma). Injury (e.g., testicular trauma). Medications to treat high blood pressure (hypertension) and Medications to treat high blood pressure (hypertension) and

digestive disease. digestive disease. Metabolic disorders such as hemochromatosis (affects how the Metabolic disorders such as hemochromatosis (affects how the

body uses and stores iron). body uses and stores iron). Systemic disease (high fever, infection, kidney disease). Systemic disease (high fever, infection, kidney disease). Testicular cancer. Testicular cancer. Varicocele. Varicocele.

Causes of male infertilityCauses of male infertility

Retrograde ejaculation: Occurs when impairment of the muscles or Retrograde ejaculation: Occurs when impairment of the muscles or nerves in the bladder neck prohibit it from closing during ejaculation, nerves in the bladder neck prohibit it from closing during ejaculation, allowing semen to flow backward into the bladder and causing infertility.allowing semen to flow backward into the bladder and causing infertility.

- It may result from bladder surgery, - It may result from bladder surgery, - Congenital defect in the urethra or bladder, Or- Congenital defect in the urethra or bladder, Or - Disease that affects the nervous system. Diminished or "dry" - Disease that affects the nervous system. Diminished or "dry"

ejaculation and cloudy urine after ejaculation are signs of this condition.ejaculation and cloudy urine after ejaculation are signs of this condition.

Testicular trauma, resulting from injury, surgery, or infectionTesticular trauma, resulting from injury, surgery, or infection

Male Partner Diagnostic TestsMale Partner Diagnostic Tests

Semen AnalysisSemen AnalysisFor sperm count and characteristics. It is obtained For sperm count and characteristics. It is obtained after three days of sexual abstinence. after three days of sexual abstinence.

Other Possible Tests:Other Possible Tests:

Blood tests, such as FSH, LH, Prolactin and a Blood tests, such as FSH, LH, Prolactin and a testosterone level may be drawn.testosterone level may be drawn.

The sperm penetration assay (SPA), or sperm-oocyte interaction The sperm penetration assay (SPA), or sperm-oocyte interaction test, examines the ability of sperm to penetrate the egg by test, examines the ability of sperm to penetrate the egg by combining it with a hamster egg. combining it with a hamster egg.

The immunobead test looks at semen for the presence of The immunobead test looks at semen for the presence of antibodies that damage sperm. antibodies that damage sperm.

Post-ejaculation urinanalysis may identify diseases that affect Post-ejaculation urinanalysis may identify diseases that affect fertility, such as kidney disease, diabetes, and repeated urinary fertility, such as kidney disease, diabetes, and repeated urinary tract infection (UTI). tract infection (UTI).

Blood tests identify disorders that impair testosterone and sperm Blood tests identify disorders that impair testosterone and sperm production. production.

Male Partner Diagnostic Tests

Six sperm factors are analyzed in semen Six sperm factors are analyzed in semen

analysisanalysis:: Concentration (sperm/milliliter; cc) Concentration (sperm/milliliter; cc) Morphology (sperm shape; normal structure Morphology (sperm shape; normal structure

associated with sperm health) associated with sperm health) Motility (or mobility; % sperm movement) Motility (or mobility; % sperm movement) Standard semen fluid test (thickness, color) Standard semen fluid test (thickness, color) Total motile count (total number of moving Total motile count (total number of moving

sperm) sperm) Volume (total volume of ejaculate) Volume (total volume of ejaculate)

Parameter Results Normal ValuesParameter Results Normal Values

Colour Gray Colour Gray Coagulate? Yes Coagulate? Yes Liquefy ? Yes Liquefy ? Yes

If yes, time in minutes < 30 If yes, time in minutes < 30 Volume (ml) 2 to 6 Volume (ml) 2 to 6 pH 7.5 to 8.0 pH 7.5 to 8.0 Sperm concentration 20-200 ( million per ml) Sperm concentration 20-200 ( million per ml) Grade of sperm motility (forward progressive) Grade of sperm motility (forward progressive)

motility > 50% motility > 50% Motile sperm count > 10 million per ml Motile sperm count > 10 million per ml White blood cells < 1 million/ml White blood cells < 1 million/ml Agglutination nil Agglutination nil Morphology > 30 % normal formsMorphology > 30 % normal forms

Semen Analysis

Female Partner Diagnostic TestsFemale Partner Diagnostic Tests

It include some or all of the following: It include some or all of the following: History History Physical Exam Physical Exam Pelvic Exam with pap smear and cultures Pelvic Exam with pap smear and cultures Uterine Measurement (by ultrasound) Uterine Measurement (by ultrasound)

Cycle Day 1,2, or 3 Blood TestsCycle Day 1,2, or 3 Blood TestsFollicle stimulating hormones (FSH)Follicle stimulating hormones (FSH) , ,Luteinizing hormone (LH)Luteinizing hormone (LH) , ,Prolactin, and Estradiol levels (E2) on either Day 1, 2, or 3 of your cycleProlactin, and Estradiol levels (E2) on either Day 1, 2, or 3 of your cycle . .N.B. Generally, Cycle Day 1 is defined as the first day of flow (i.e. not N.B. Generally, Cycle Day 1 is defined as the first day of flow (i.e. not spotting). These are baseline hormones that give us an idea of how spotting). These are baseline hormones that give us an idea of how sensitive the ovaries are to fertility drugssensitive the ovaries are to fertility drugs . .

N.B. Hormonal level vary according to phase of the cycle or from lab to N.B. Hormonal level vary according to phase of the cycle or from lab to lablab..

Thyroid panelThyroid panel is also done since an abnormal is also done since an abnormal thyroid level may interfere with normal ovulation. thyroid level may interfere with normal ovulation.

Female Partner Diagnostic TestsFemale Partner Diagnostic Tests

LH SurgeLH Surge//Ovulation:Ovulation: Usually on Cycle Day 10 (10 days from the first day of your menses). Usually on Cycle Day 10 (10 days from the first day of your menses).

Positive result, means ovulation within 24-36 hoursPositive result, means ovulation within 24-36 hours.. Progesterone Level:Progesterone Level:

It is a blood test drawn seven (7) days after ovulation. A level of above It is a blood test drawn seven (7) days after ovulation. A level of above 10 ng/ml indicates a healthy ovulation. 10 ng/ml indicates a healthy ovulation.

Post Coital TestPost Coital TestThis tests for the sperm’s ability to penetrate the cervical mucus. It is This tests for the sperm’s ability to penetrate the cervical mucus. It is performed like a pap test on the female partner the day before performed like a pap test on the female partner the day before ovulation. ovulation.

Preparation: Preparation: Normal sexual relations (without the use of lubricants) the night of your Normal sexual relations (without the use of lubricants) the night of your

LH surge. Six to 12 hours after intercourse. LH surge. Six to 12 hours after intercourse.

Female Partner Diagnostic Tests

Sonohysterogram Sonohysterogram (water ultrasound)(water ultrasound)This is a test to examine the uterine cavity for abnormalities, This is a test to examine the uterine cavity for abnormalities, such as polyps or fibroids. It is performed between cycle day 6-such as polyps or fibroids. It is performed between cycle day 6-12. It takes approximately 10 minutes and is associated with 12. It takes approximately 10 minutes and is associated with minimal discomfort. minimal discomfort.

Other Possible TestsOther Possible TestsAndrogens (DHEA-S, testosterone).Androgens (DHEA-S, testosterone).

Female Partner Diagnostic Tests

Normal Karyotype

Genetic Tests of InfertilityGenetic Tests of Infertility

MenMen take tests that look for: take tests that look for: Changes in chromosome structure or number Changes in chromosome structure or number Missing regions on the Y chromosome (also called Missing regions on the Y chromosome (also called

Y deletion) Y deletion) Changes in the cystic fibrosis gene Changes in the cystic fibrosis gene

WomenWomen take tests that look for: take tests that look for: Changes in chromosome structure or number. Changes in chromosome structure or number. Changes in the Fragile X region of the X Changes in the Fragile X region of the X

chromosome.chromosome.

Men who are unaffected with CF, but carry a single copy Men who are unaffected with CF, but carry a single copy of the gene (a "carrier" for CF), are at high risk of of the gene (a "carrier" for CF), are at high risk of "congenital absence of the vas deferens." Men with "congenital absence of the vas deferens." Men with this condition do not have sperm in the ejaculate, but this condition do not have sperm in the ejaculate, but have abundant sperm in epididymus and testicle, have abundant sperm in epididymus and testicle,

which is retrievable for IVF and ICSIwhich is retrievable for IVF and ICSI . .

All men with congenital absence of the vas deferens All men with congenital absence of the vas deferens should be tested for CF gene mutations. Their female should be tested for CF gene mutations. Their female partners need to be tested in order to know whether or partners need to be tested in order to know whether or not the couple will be at risk to have a child with the not the couple will be at risk to have a child with the diseasedisease..

Single-gene Defects and Infertility (mutation in the gene that causes the disease Cystic Fibrosis:(

Genetic & InfertilityGenetic & Infertility

However, research work have reported that about 10-15% of men However, research work have reported that about 10-15% of men with severe male factor infertility (less than 2 million sperm per with severe male factor infertility (less than 2 million sperm per cc), when specifically tested, will be found to have a small cc), when specifically tested, will be found to have a small portion of genetic material (DNA) missing from the Y portion of genetic material (DNA) missing from the Y chromosome. This is a particular type of single-gene mutation chromosome. This is a particular type of single-gene mutation that is associated with low sperm counts or lack of any sperm in that is associated with low sperm counts or lack of any sperm in the ejaculate. It does not appear that this deletion is associated the ejaculate. It does not appear that this deletion is associated with any abnormality other than male infertility. Many men have with any abnormality other than male infertility. Many men have been able to conceive with this condition through IVF with ICSIbeen able to conceive with this condition through IVF with ICSI..

Y-Chromosome Partial DeletionsGenetic & InfertilityGenetic & Infertility

Ovary gene may explain certain aspects of Ovary gene may explain certain aspects of infertilityinfertility

Ovary gene whose absence from mouse egg cells produced Ovary gene whose absence from mouse egg cells produced severe pregnancy complications. severe pregnancy complications.

The gene, Fmn2The gene, Fmn2, , which produces the protein formin-2, is which produces the protein formin-2, is similar in mice and humans and offers promise for similar in mice and humans and offers promise for understanding embryo loss, birth defects, and infertility in understanding embryo loss, birth defects, and infertility in women. women.

The study appears in the December Nature Cell Biology. The study appears in the December Nature Cell Biology.

Genetic &InfertilityGenetic &Infertility

http://mend.endojournals.org/content/vol13/issue6/images/large/mg0690301001.jpeg

Schematic Representation of the Hypothalamic-Pituitary-Gonadal Axis and Anterior Pituitary Development Mutations in genes reported to affect fertility or gonadal development in humans white boxes.

Reported Mutations in the FSH and LH ß-Subunits (top panel) and Inactivating Mutations of the FSH/LH Receptor (composite diagram, lower panel) For clarity, activating mutations of the LH receptor and FSH

receptor are not depicted.

Gene Gene ((GlcNAc-6-OSTGlcNAc-6-OST)) gets transcribed and gets transcribed and then translated into a protein and this particular then translated into a protein and this particular protein functions as an enzyme,protein functions as an enzyme," "" "It has been shown It has been shown to be expressed specifically during the window of to be expressed specifically during the window of implantation, that this particular gene, for no reason, is implantation, that this particular gene, for no reason, is abnormally expressed in women with endometriosis abnormally expressed in women with endometriosis which results in the embryo not being able to find the which results in the embryo not being able to find the appropriate place to bind to the endometrium leading appropriate place to bind to the endometrium leading to a failure or defect in the implantation processto a failure or defect in the implantation process." ."

References: http://www.endometriosis.org/References: http://www.endometriosis.org/

Genetic & InfertilityGenetic & Infertility

The development of The development of IVFIVF has allowed many couples to has allowed many couples to have the families they may otherwise have been have the families they may otherwise have been

unable to haveunable to have . .

At the same time, this technology has also allowed At the same time, this technology has also allowed researchers to begin to study the researchers to begin to study the genetic make-upgenetic make-up of of

the earliest stages of embryosthe earliest stages of embryos . .

These advances are providing some insights into how These advances are providing some insights into how genetics and infertility might be linked, just beginning genetics and infertility might be linked, just beginning to understand how defects (mutations) in specific to understand how defects (mutations) in specific

genes may result in male and female infertilitygenes may result in male and female infertility..

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References & Online Further References & Online Further ReadingReading

httphttp://://wwwwww..dnadirectdnadirect..comcom//teststests//infertilityinfertility//karyotypekaryotype..jspjsp http://www.infertilitydoctor.com/welcome/welcome_intro.htmhttp://www.infertilitydoctor.com/welcome/welcome_intro.htm http://www.eurekalert.org/pubnews.phphttp://www.eurekalert.org/pubnews.php http://urologychannel.com/whfc/lab.shtml#analysishttp://urologychannel.com/whfc/lab.shtml#analysis http://www.ivf-infertility.com/infertility/index.phphttp://www.ivf-infertility.com/infertility/index.php http://www.drmalpani.com/index.htmlhttp://www.drmalpani.com/index.html http://www.ktvb.com/http://www.ktvb.com/ http://www.bcm.edu/fromthelab/index.htmhttp://www.bcm.edu/fromthelab/index.htm