GENETICS AND INFERTILITY

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GENETICS AND INFERTILITY

• BY
• Salwa Hassan Teama
• M.D. Clinical Pathology Oncology Laboratory
  Medicine, National Cancer Institute, Cairo
  University

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INFERTILITY

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

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Timely Evaluations

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

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Helping you build your family
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True Infertility

• True infertility only occurs in a few specific
  situations
• Women with blocked fallopian tubes.
• Women that has no uterus or no egg follicles
  (menopause or premature ovarian failure).
• Men who have no sperm.
• In these situations, successful conception
  will only occur with the use of specific medical
  technology, Sometimes the use of a third party is
  necessary to provide eggs, sperm or a uterus to
  carry the pregnancy.

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Sub-Fertility

• Any other diagnoses in couples, besides the
  mentioned above, consider some degree of
  sub-fertility. That is, there is some chance,
  even small, of conception without the assistance
  of fertility treatments.
• A diagnostic evaluation may uncover a problem
  that can be overcome with medical technology.
  However, The role of the fertility specialist in
  this case is to guide the patient towards timely
  evaluations and treatment decisions that will
  significantly improve their chances of becoming
  parents.

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Causes and Risk Factors

• The primary causes of male infertility are
• Impaired sperm production,
• Impaired sperm delivery, and
• Testosterone deficiency (hypogonadism).
• Infertility can result from a condition that is
  present at birth (congenital) or that develops
  later (acquired).
• Causes of infertility include the following
• Chemotherapy
• Defect or obstruction in the reproductive system
  such as failure of testes to descend into the
  scrotum (cryptorchidism) or absence of one or
  both testicles (anorchism)
• Disease (e.g., cystic fibrosis, sickle cell
  anemia, sexually transmitted diseases STDs)

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Causes and Risk Factors

• Hormone dysfunction (testosterone deficiency
  caused by a disorder in the hypothalamic-pituitary
  -gonadal axis)
• Infection (e.g., prostatitis, epididymitis,
  orchitis can cause irreversible infertility if
  they occur before puberty)
• Injury (e.g., testicular trauma)
• Medications to treat high blood pressure
  (hypertension) and digestive disease
• Metabolic disorders such as hemochromatosis
  (affects how the body uses and stores iron)
• Systemic disease (high fever, infection, kidney
  disease)
• Testicular cancer
• Varicocele

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Retrograde ejaculation

• occurs when impairment of the muscles or nerves
  in the bladder neck prohibit it from closing
  during ejaculation, allowing semen to flow
  backward into the bladder and causing
  infertility.
• It may result from bladder surgery,
• a congenital defect in the urethra or bladder,
• or disease that affects the nervous system.
  Diminished or "dry" ejaculation and cloudy urine
  after ejaculation are signs of this condition.
• Testicular trauma, resulting from injury,
  surgery, or infection can trigger an immune
  response in the testes that may damage sperm.
  Though their effects are not fully understood,
  antibodies can impair the ability of sperm cells
  to swim through cervical mucus or to penetrate a
  female egg.

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Male Partner Diagnostic Tests

• Semen AnalyisFor sperm count and
  characteristics. It is obtained after three days
  of sexual abstinence. The sample needs to be kept
  at room to body temperature and transported to
  the laboratory within one hour.
• Other Possible Tests
• Blood tests, such as FSH, LH, Prolactin and a
  testosterone level may be drawn.

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Male Partner Diagnostic Tests

• The sperm penetration assay (SPA), or
  sperm-oocyte interaction test, examines the
  ability of sperm to penetrate the egg by
  combining it with a hamster egg.
• The immunobead test looks at semen for the
  presence of antibodies that damage sperm.
• Post-ejaculation urinanalysis may identify
  diseases that affect fertility, such as kidney
  disease, diabetes, and repeated urinary tract
  infection (UTI). Blood tests identify disorders
  that impair testosterone and sperm production.

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Six sperm factors are analyzed in semen analysis

• Concentration (sperm/milliliter cc)
• Morphology (sperm shape normal structure
  associated with sperm health)
• Motility (or mobility sperm movement)
• Standard semen fluid test (thickness, color)
• Total motile count (total number of moving sperm)
  
• Volume (total volume of ejaculate)

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Semen Analysis

• Parameter Results /Normal Values
• Colour
• Gray
• Coagulate? Yes
• Liquefy ? Yes If yes, time in minutes lt 30
• Volume (ml) 2 to 6
• pH 7.5 to 8.0
• Sperm concentration 20-200 ( million per ml)
• Grade of sperm motility Grade a,b ( forward
  progressive) motility gt 50
• Motile sperm count gt 10 million per ml
• White blood cells lt 1 million/ml
• Agglutination nil
• Morphology gt 30 normal forms

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Normal Hormone Values for men

• Testosterone 300 - 1100 ng/dlProlactin 7 - 18
  ng/mlLuteinising Hormone ( LH) 2 - 18
  mIU/mlFollicle Stimulating Hormone ( FSH) 2 -
  18 mIU/mlEstradiol ( Day 3) lt 50 pg/ml

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• Female Partner Diagnostic Tests

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Diagnostic Studies

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

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Female Partner Diagnostic Tests

• Cycle Day 1,2, or 3 Blood Tests
• Follicle stimulating hormones (FSH),
• Luteinizing hormone (LH),
• Prolactin, 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 spotting). These are
  baseline hormones that give us an idea of how
  sensitive the ovaries are to fertility drugs.
• N.B.Hormonal level vary according to phase of the
  cycle or from lab to lab.
• Thyroid panel is also done since an abnormal
  thyroid level may interfere with normal
  ovulation.

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Female Partner Diagnostic Tests

• LH Surge/Ovulation
• Usually on Cycle Day 10 (10 days from the first
  day of your menses)
• When you have a positive result, you will
  ovulate within 24-36 hours.

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Female Partner Diagnostic Tests

• Post Coital TestThis tests for the sperms
  ability to penetrate the cervical mucus. It is
  performed like a pap test on the female partner
  the day before ovulation. We will request that
  you have normal sexual relations (without the use
  of lubricants) the night of your LH surge (using
  an ovulation predictor kit). Six to 12 hours
  after intercourse.

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Female Partner Diagnostic Tests

• Progesterone LevelProgesterone is a hormone
  made by the corpus luteum (the follicle that
  released the egg). It is responsible for
  maintaining a healthy endometrial lining to
  support a pregnancy. It is a blood test drawn
  seven (7) days after ovulation. A level of above
  10 ng/ml indicates a healthy ovulation.

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• Sonohysterogram (water ultrasound)This is a test
  to examine the uterine cavity for abnormalities,
  such as polyps or fibroids. It is performed
  between cycle day 6-12. It takes approximately 10
  minutes in the office and is associated with
  minimal discomfort.
• Other Possible TestsAndrogens (DHEA-S,
  testosterone) may be drawn.

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• GENETICS AND INFERTILITY

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NORMAL KARYOTYPE
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• It is possible that many cases of unexplained
  infertility will one day be found to have a clear
  genetic basis.

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CHROMOSOMAL ABNORMALITY
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CHROMOSOMAL ABNORMALITY
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GENETIC TESTS OF INFERTILITY

• These tests are safe and clinically accurate.

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GENETIC AND INFERTILITY

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

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Single Gene Disorders in the Hypothalamic-Pituitar
y-Gonadal Axis Resulting in Impaired Fertility

• AHC (DAX1)Xp21Orphan nuclear hormone receptor57
  /66MAdrenal failure, HHG (hemizygous)
• KALXp22Extracellular matrix protein25 /34MHHG,
  anosmia/- unilateral renal agenesis, synkinesia
  (hemizygous)
• GNRHR4q21G-protein coupled receptor4 /4MDelayed
  puberty, hypogonadism, severe oligospermiaFDelayed
  puberty, variable thelarche, amenorrhea
• HESX13p21Paired-like homeodomain TF1
  /1M/FSepto-optic dysplasia, panhypopituitarism

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Figure 1. Schematic Representation of the
Hypothalamic-Pituitary-Gonadal Axis (main figure)
and Anterior Pituitary Development (inset)
Mutations in genes reported to affect fertility
or gonadal development in humans white boxes.
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Figure . 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.
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GENETIC AND FEMALE INFERTILITY

• Ovary gene may explain certain aspects of
  infertility
• Ovary gene whose absence from mouse egg cells
  produced severe pregnancy complications. The
  gene, Fmn2, which produces the protein formin-2,
  is similar in mice and humans and offers promise
  for understanding embryo loss, birth defects, and
  infertility in women.
• The study appears in the December Nature Cell
  Biology.

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Figure . A human egg after collection from the
ovary

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GENETIC AND FEMALE INFERTILITY

• NPM2 is actually involved in infertility, a woman
  with a loss of NPM2 function might never know she
  had a fertility problem .
• In many women, infertility is unexplained, and
  defects in this gene might be accountable for
  some of that, The gene seems to be very important
  because it can be found in animals up and down
  the evolutionary tree, from humans to mice to
  frogs.
• NPM2 is one of only three known maternal effect
  genes in mammals. It is important in the
  organization of the nucleus and the nucleolus (an
  organelle in the nucleus involved in the
  transcription or biological translation of a
  particular form of RNA).

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Infertility researchers identify one gene's
critical role in the human embryo implantation
process

• This gene (GlcNAc-6-OST) gets transcribed and
  then translated into a protein and this
  particular protein functions as an enzyme,"
• "It has been shown to be expressed specifically
  during the window of implantation, that this
  particular gene, for a yet-to-be-uncovered
  reason, is abnormally expressed in women with
  endometriosis which results in the embryo not
  being able to find the appropriate place to bind
  to the endometrium leading to a failure or defect
  in the implantation process."
• REFRENCES http//www.endometriosis.org/

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• GENETICS AND MALE INFETILITY

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GENETIC AND INFERTILITY

• Men take tests that look for
• Changes in chromosome structure or number
• Missing regions on the Y chromosome (also called
  Y deletion)
• Changes in the cystic fibrosis gene
• Which tests are appropriate for you depends on
  your personal history and what you know about
  your fertility.

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GENETICS AND MALE INFETILITY

• Genetic defects are related to male
  infertility and "unexplained" infertility. As
  more genes are identified that play a role in
  reproduction, defects in these genes will be
  discovered.
• ICSI (intra cytoplasmic sperm injection) has
  provided the ability to overcome some of these
  defects for the current generation seeking to
  have their own genetic children but may mean
  continued infertility for the next generation.

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

• Some genetic defects, instead of involving an
  entire chromosome, affect a single gene. An
  example of this is the most common mutation seen
  in the Caucasian population, a mutation in the
  gene that causes the disease Cystic Fibrosis.
• Men who are unaffected with CF, but carry a
  single copy of the gene (a "carrier" for Cystic
  Fibrosis), are at high risk to have a condition
  called "congenital absence of the vas deferens."
  Men with this condition do not have sperm in the
  ejaculate, but have abundant sperm in the
  epididymus and testicle, which is retrievable for
  IVF and ICSI. This is an example of a single-gene
  mutation that results in a specific type of male
  infertility. All men with congenital absence of
  the vas deferens should be tested for CF gene
  mutations. Their female partners need to be
  tested in order to know whether or not the couple
  will be at risk to have a child with the disease.

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Y-Chromosome Partial Deletions

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

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Y-Chromosome Partial Deletions

• A recent scientific presentation reported that
  of ten babies born to fathers with known partial
  Y chromosome deletions, all the male babies
  studied had the same deletion as their fathers.
  That is, they will also be likely to be
  infertile. Although preliminary, it does not
  appear that this deletion is worse in the
  children, That is, there is no finding of larger
  pieces of missing DNA in the sons, therefore, no
  evidence that the abnormality is getting worse
  with a subsequent generation

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IN VITRO FERTELIZATION

• The development of IVF has allowed many couples
  to have the families they may otherwise have been
  unable to have. At the same time, this technology
  has also allowed researchers to begin to study
  the genetic make-up of the earliest stages of
  embryos. These advances are providing some
  insights into how genetics and infertility might
  be linked, just beginning to understand how
  defects (mutations) in specific genes may result
  in male and female infertility.

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Preimplantation Genetic Diagnosis

• The Preimplantation Genetic Diagnosis (PGD)
  technique requires the use of the test tube baby
  technique (IVF) to test embryos for genetic
  disorders before it implants in the womb
  (uterus). It avoids the need for abortion. The
  procedure is associated with ethical and medical
  concerns and raises issues of sex selection and
  genetic engineering

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REFRENCES

• http//www.dnadirect.com/tests/infertility/karyoty
  pe.jsp
• http//www.infertilitydoctor.com/welcome/welcome_i
  ntro.htm
• http//www.eurekalert.org/pubnews.php
• http//urologychannel.com/whfc/lab.shtmlanalysis
• http//www.ivf-infertility.com/infertility/index.p
  hp
• http//www.drmalpani.com/index.html
• http//www.ktvb.com/
• http//www.bcm.edu/fromthelab/index.htm

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THANKN YOU

• THANKN YOU