Genetic Reproduction

Eva Diah Setijowati

Differences in gametogenesis
Male Female
Initiation Puberty Early embryonic
life
Duration cca 72 days 10-50 years
Numbers of mitoses 30 - 500 20-30
in gamete formation
Gamete production 4 spermatids 1 ovum+3 polar
bodies

Gamete production 100-200 million 1 ovum per

menstrual
per ejaculate cycle
Degeneration of germ cells in ovary

5th month of fetal life 7 x 106 of cells

time of birth 2 x 106 of cells

puberty 200 000 of cells

ovulated 400 of cells

Long period between M I and ovulation = factor of high

probability of nondisjunction
 Consequences of meiosis
1. reduction of diploid chromosomal number to haploid

2. segregation of alleles in M I, M II (2st Mendel´s law)

3. random assortment of homologues – random

combination maternal and paternal chromosomes in

gametes (3nd Mendel´s law)

4. increase of genetic variability by crossing-over

(chromatids with segments of maternal and paternal origin)

Genetic determination of sex

23,X

23,X

23,Y
Infertility : Definition
 Infertility is the inability of a sexually
active, non-contracepting couple to
achieve pregnancy in one year
(WHO.,2000)
 About 15% of couples do not achieve
pregnancy within 1 year and seek medical
treatment for infertility
 Infertility affects both men and women.
 Affect one in six couples
 A physical cause can be identified in 90%
of cases: 30% in males, 60% in females
Causes of Infertility
GENETIC DISORDERS IN
INFERTILITY
 Chromosomal abnormalities
 Sperm chromosomal abnormalities
 Sex chromosome abnormalities (Klinefelter’s syndrome
and variants [47,XXY; 46,XY/ 47,XXY mosaicism])
 Autosomal abnormalities
 Translocations
 Genetic defects
 X-linked genetic disorders and male fertility
 Kallmann’s syndrome
 Mild Androgen Insensitivity syndrome
 Other X-disorders
Primary Infertility and Genetics
 Sex chromosome anomalies
-Numerical :ex : 47,XXY , 45 X
-Structural :ex : deletions of X or Y
 Autosomal chromosome anomalies
-Structural :ex : Translocations
 Single Gene disorders
-autosomal dominant : Steinert Myotonic
Dystrophy in males
-autosomal recessive :Cystic Fibrosis
-X-linked :Androgen Resistance
Secondary Infertility and Genetics
 Sex chromosome anomalies
 -Numerical :ex : mosaics XY/XXY or X/XX
 Autosomal chromosome anomalies
 -Structural :ex : translocations, inversions
 Single Gene disorders
-autosomal dominant :Steinert Myotonic
Dystrophy in females
-autosomal recessive :Sickle cell anaemia
-X-linked :Fragile X syndrome
Genetic causes of Male and Female
Infertility:
I Hypothalamic
→KAL1 gene(XLR hypogonadotrophic
hypogonadism in males)
→AHC gene(XLR cong.adrenal hypoplasia
in males)
II Pituitary
→GNRHR gene(AR gonadotrophin
releasing hormone receptor)
→FSHβgene, LHβand hCGβgene complexe
Successful therapy for pituitary causes =
replace missing trophic factor (LH, FSH)
 Con’t
III Gonadal(major factor)
→Genes
involved in Gonadotrophin receptors, steroid
hormone receptors, steroid synthesis (poor
prognosis →donor), autosomal genes (SOX9,
WT1 can cause sexual ambiguity+infert.)
→X Chromosomal causes :
-whole X deletions (45,X cell line with/without
mosaicism (46,XY/ 46,XX/ 47,XXX), when
fertile beware POF -partial X deletions (Xp11,
Xp21, Xq13 putative POF1 region, Xq26
putative POF2 region
-X;autosome translocations (rare)
 Con’t
IV Outflow tract
→ Androgene receptor gene(AR)
46,XY male with androgene insensitivity
→female phenotype)
→CFTR gene: cystic fibrosis (AR)
congenital bilateral absence of vas deferens
found in 1-2 % infertile males, around 90% of
which carry one or two CFTR mutations :
normal but immotile testicular sperm
→reproduction by biopsy+ICSI.
Test partner + Genetic counseling, other family
members at risk?
→HOXA 13 gene
only known single gene causing uterine
anomalies
In male:
•Chromosomal abnormality →15 % (azoo),
5 % (oligo)
•De novo deletion of azoosp factor region
(AZF) →13% (a/oligo)
•Cong. Bilat. Abs. of vas deferens (CBAVD)
→1-2% (azoo)
Currently Gene and Chromosomal
abnormalities are known to affect count
and motility, yet unknown gene mutations
are expected to affect morphology
Y chromosome and male infertility
 Clinical implications of Y microdeletions
o The highest frequency is found in azoospermic men (8-
12%) followed by oligospermic (3-7%) men
o The most frequently deleted region is AZFc
(approximately 65-70%), followed by deletions of the
AZFb and AZFb+c or AZFa+b+c regions (25-30 %)
whereas deletions of the AZFa region are extremely rare
(5%)
o The complete removal of the AZFa and AZFb regions are
associated with severe testicular phenotype, Sertoli Cell
Only syndrome and spermatogenic arrest
o The complete removal of the AZFc region causes a
variable phenotype which may range from azoospermia
to oligozoospermia
Autosomal defects with severe
phenotypic abnormalities and
infertility
Genetic Consultation in Infertility
Genetic testing
•Identify the etiology
•Identify syndromic causes of reproduction failure

Genetic counseling
•Implications of syndromic causes
•Other family members at risk? Offer counseling
•Expose reproduction options (donor, adoption), ART
methods (Artif.reprod.techniques): IVF, ICSI, chances
of success, technique, limits, genetic risks…
•Prenatal Diagnosis
•Risk / implications of transmission (ex. Y
microdeletion)
•Psychological and ethical implications
GENETIC OPTIONS FOR
INFERTILIY
Assisted Reproductive Technologies
(ARTs)

- Intrauterine insemination
- Surrogate motherhood
- In vitro fertilization (IVF)
- Gamete intrafallopian transfer (GIFT)
- Zygote intrafallopian transfer (ZIFT)
- Oocyte banking and donation
- Preimplantation genetic diagnosis
Normal Sperm Morphology
Abnormal Morphology
Abnormal Semen Analysis
 Azospermia  Oligospermia
◦ Klinefelter’s (1 in ◦ Anatomic defects
1000) ◦ Endocrinopathies
◦ Hypogonadotropic- ◦ Genetic factors
hypogonadism
◦ Exogenous (e.g.
◦ Ductal obstruction heat)
(absence of the Vas
deferens)  Abnormal volume
◦ Retrograde
ejaculation
◦ Infection
◦ Ejaculatory failure
Egg Retrieval
In Vitro Fertilization (IVF)
Fertilization
Embryo Transfer
How Many Embryos are
Transferred?

 Related to age and embryo quality

◦ <35 = 2
◦ 35-37 = 2-3
◦ 38-40 = 3-4
◦ >40 = up to 5

◦ For patients with 2 or more failed IVF

cycles, or a poor prognosis, can add more
based on clinical judgment
What Happens to the Other
Embryos?

 Freeze Embryos
 Donate For Research/Stem Cells
 Embryo Adoption
 Discard
Special IVF Procedures
 Assisted hatching
 Intracytoplasmic sperm injection
(ICSI)
 Preimplantation genetic diagnosis
(PGD)
 Freezing
 Egg donation
 Surrogacy
Assisted Hatching
In vitro Fertilization (IVF)
For in vitro fertilization, a sperm fertilizes an
oocyte in a culture dish
Embryos are transferred to the oocyte
donor’s uterus (or a surrogate’s uterus) for
implantation
1978: First IVF child born (Louise Joy
Brown)
- Since then, 4 million IVF children
Intracytoplasmic sperm injection (ICSI) is
more effective than IVF alone
Intracytoplasmic Sperm Injection

For cases in which sperm cannot penetrate

the oocyte, IVF can be accompanied by
ICSI which injects sperm directly into the
oocyte

ICSI allows conception in cases of low

sperm count, abnormal sperm shape,
sperm motility problems,
- And in cases where male has spinal
cord injuries and cannot ejaculate
Intracytoplasmic Sperm Injection

Figure 21.3
Preimplantation Genetic
Diagnosis (PGD)
1989: First children who had PGD
- Used to select females who could not
inherit X-linked disease from mother
1992: First child born following PGD to
screen for cystic fibrosis allele present in
her family
PGD can be combined with IVF for women
who have had multiple miscarriages
Preimplantation Genetic
Diagnosis (PGD)
This PGD technique allows detection of
genetic and chromosomal abnormalities
prior to implantation

One cell or blastomere of an 8-celled

embryo can be removed for testing
- The remaining cells will complete
normal development

About 29% success rate

The Science of PGD

 PGD combines recent advances in genetics and

reproductive medicine, “reprogenetics”

 Requires IVF cycle

◦ ovarian stimulation
◦ egg harvest
◦ In vitro fertilisation

 Embryo Biopsy
Embryo biopsy

 Removal of one or two cells

from a day three eight cell
pre-embryo

 Genetic testing:
-fam single gene disorder
-fam chromosomal
disorders
-Aneuploidy
Reproductive Opportunities
 Diagnosis of heritable disorder (gene mutations,
chromosomal disorder) at preimplantation stage
Alternative options:
-take chances with pregnancy
-prenatal diagnosis with option of
termination
-utilise donor gametes and IVF
-remain childless, adopt
 PGD with Aneuploidy Screening
-infertility / recurrent miscarriage
-risks associated with reproductive age