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Human Fertility Summary (NWI-BM050B) Radboud University
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Detailed summary of the lectures and extras from the course: Human fertility.
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SUMMARY OF THE COURSE HUMAN FERTILITY2022 Msc
ELISE REUVEKAMP Medical
Biology
Q4 2022
Human Fertility
,Content
Lecture 1: Sexual Differentiation and Germline......................................................................................2
Video: Sex, Gender and sexual differentiation...................................................................................9
Assignment questions.......................................................................................................................10
Lecture 2: Oogenesis............................................................................................................................11
Lecture 3: Spermatozoa, oocytes and fertilization...............................................................................17
Opinion paper/review assignment...................................................................................................23
Questions quiz:.................................................................................................................................24
Lecture 4: Spermatogenesis.................................................................................................................25
Papers related to spermatogenesis..................................................................................................29
Lecture 5: Genetics of infertility...........................................................................................................31
Video: Paternal age effect................................................................................................................36
Video: IVF has no detrimental effect on the genome of fetal and placenta lineages.......................36
Lecture 6: Medically assisted reproduction..........................................................................................37
Selection of embryos assignment.....................................................................................................42
ICSI and outcome assignment...........................................................................................................42
Lecture 7: Cryopreservation and human production............................................................................43
Lecture 8: Ethical and societal aspects of human fertility....................................................................47
General information from poster presentations..................................................................................48
1
,Lecture 1: Sexual Differentiation and Germline
Sexual determination is the designation for the development stage towards either male or female,
which starts at fertilization (genotypic differentiation). Whereas, sexual differentiation is the
pathway towards the development of the phenotype (phenotypic differentiation). Sexual
differentiation of the brain and secondary characteristics at puberty.
The process of sex determination in mammals normally unfolds in three distinct stages
1) Establishment of chromosomal sex at fertilization (XX or XY)
2) Commitment to the pathway of gonadal differentiation with respect to chromosomal sex,
through the action (or absence) of the Y chromosome gene SRY
3) Correct development of secondary sexual characteristics, including internal and external
genitalia, in accordance with gonadal sex.
At any of these three steps, the process of sex determination can go wrong, leading to disorders of
sexual development. We can also consider aberrant mammalian sex determination, focusing on
examples of sex reversal stemming from gene defects.
In mammals an XX is a female and XY a male. This is different in birds, a female is XY (or ZW) and a
male is XX (or ZZ). There are also differences with insects, which is determined by the presence or
absence of two X chromosomes (female = XX, male = XO) or haploid/diploid, where the male is
haploid and female diploid.
Sexual differentiation is also dependent on other factors, such as temperature. Some reptiles,
including crocodiles and turtles do not have sex chromosomes. The chance that a crocodile hatches a
male or female is not 50/50 as in humans, but it is temperature/climate dependent, this is called
temperature-dependent sex determination. If the temperatures surrounding the nest are very high
or low, the embryos will be female, whereas anything in the middle (between 31-34°C) will result
into male crocodiles. Climate change will therefore greatly impact the temperature-dependent sex
determination.
The SRY gene
In 1959 it was established that the femaleness and maleness in
humans depends on the presence of the Y-chromosome.
The Y-chromosome contains the SRY gene, which stands for sex
determining region of the y chromosome. It has an influence on
gonadal differentiation, as it encodes for transcription factors
(such as Sox9) that can regulate genes, controlling the
development of the testes. Specifically, the Sox9 can act to help
stromal cells to differentiate into Sertoli cells.
It is a member of the Sox family of transcription factors, which
encodes for a 223-aminoacid non-histone protein. SRY has a
highly conserved 79-aa DNA binding region and is located in the
homologous region making it susceptible to translocation to X-
chromosome. Expression of the SRY gene product occurs in the
gonadal tissue at the time of sex differentiation.
2
, In the absence of the Y-chromosome, there is also no SRY gene and thus no development of the
testes, resulting in a female. A SRY-knockout causes an ovary to develop.
Differences between sexual differentiation and sexual determination
The SRY genes are already transcribed before implantation in the uterus (7 days after fertilization).
Also, XY embryos develop more rapidly than XX embryos, but it is only a few minutes difference.
At fertilization XX or XY embryos are indistinguishable. Then at the embryonic phase it could be seen
with some staining’s that there is a difference, due to X-inactivation in XX embryos (but
morphologically indifferent). At week 6-7 after fertilization primordial germ cell migration starts,
which is the start of the phenotypic differentiation. So, gonads are developed and there is
differentiation of external genitalia.
At this stage, the mother hardly knows that she is pregnant, and pollutants or medication could have
an impact on this phenotypic differentiation. Many problems that are observed in the clinic occur in
this early stage of the pregnancy.
The sexual differentiation of the brain and secondary characteristics start at puberty (behaviour).
Timeline and dynamics of germ cell development in rodents
- Germ cells start
developing shortly after fertilization when a population of pluripotent cells give rise to
primordial germ cell (PGC) in the epiblast. PGCs emerge from the epiblast as clusters of about
20 cells that settle in the fetal gonads. They rapidly proliferate and migrate to the genital
ridge, where sex determination occurs. PGCs stops dividing at E13.5 and gives rise to
mitotically arrested prospermatogonia (gonocytes).
- The first wave of spermatogenesis begins shortly after birth in the testis and lasts about 35
days in rodents. Prospermatogonia develop into spermatogonial stem cells (SSCs), which are
self-renewing cells that are maintained throughout life.
- SSCs proliferate by consecutive mitotic divisions and mature into spermatocytes during the
first postnatal week.
- Spermatocytes then enter meiosis until around postnatal day 19 (P19) and cross the blood-
testis barrier established by Sertoli cells.
- Round spermatids, the earliest post-meiotic cells, are produced around weaning (P20-P22).
They turn into elongating spermatids within 2-3 weeks, during which most histones (90-95%
in humans – 95-99% in mice) are replaced by transition proteins. Transition proteins are then
replaced by protamine’s for chromatin compaction.
- Spermatids mature into sperm cells, which are released into the lumen of the seminiferous
tubules from approximately P35 in mice (P44 in rats). Whereas late spermatids are
transcriptionally active, elongating spermatids and sperm cells are inactive. Bars at the
bottom indicate chromatin remodeling and cytoplasmic RNA granules including processing
3
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