L23 - Reproductive Agein

How has age at childbirth changed over time and why does it matter?

• Age at childbirth has steadily increased since the 1970s

• Average age ↑ from ~26 → >31 years

• Driven by societal factors (education, careers, choice)

• Your notes:

  • Increase largely due to choice

  • Important because fertility declines with age

How does female fertility change with age?

• Fertility gradually declines with age

• Relatively stable until ~37 years

• Then sharp decline

• Based on natural fertility populations (no contraception)

  • Gradual decline until 37

  • Real-life fertility harder to measure (people don’t try continuously)

  • Data from communities with early/continuous childbearing

How does miscarriage risk change with female age?

• Risk of miscarriage increases with age

• Relatively low in 20s–early 30s

• Sharp increase from ~37 years

• Very high risk in 40s+

• Your note:

  • At ~37 → sharp jump in pregnancies ending in miscarriage

How is nuclear DNA transmitted during fertilisation?

• Egg and sperm each contribute one haploid set of chromosomes

• Fertilised egg → diploid genome (one copy from each parent)

What is aneuploidy and how does it relate to female ageing?

• Aneuploidy = incorrect number of chromosomes

• ~95% originates from the maternal side

• Caused by errors during oocyte division

• Increases with maternal age

• Sharp rise from ~age 37

  • Often due to errors in female genome transmission

  • Dramatic increase with age

What are the reproductive consequences of aneuploidy?

• Embryos may fail before implantation → infertility

• Embryos may fail after implantation → miscarriage

• Some survive → congenital abnormalities

• Can occur at multiple stages of development

Why can aneuploidy often go unnoticed?

• Early embryo loss may occur before pregnancy is recognised

• Failure can happen at any stage (pre- or post-implantation)

• Your notes:

  • Problems can occur at any step

  • May not even be recognised

Are some chromosomes more prone to aneuploidy than others?

• Yes — error rates vary by chromosome

• Some chromosomes are more prone to errors (e.g. highlighted ones)

• No chromosome is error-free

• Based on IVF embryo/oocyte data

  • Identified from embryos that failed to progress

  • Shows which chromosomes most likely to go wrong

  • Data from IVF populations (fertility issues)

How does trisomy risk change with maternal age?

• Trisomy = extra copy of a chromosome

• Risk increases with maternal age

• Sharp rise from ~37 years

  • Incidence increases dramatically at 37

What are the most common autosomal trisomies and their outcomes?

• Trisomy 16: most common cause of miscarriage

• Trisomy 18 (Edwards): often reaches term but early death

• Trisomy 21 (Down’s): compatible with life

How has the prevalence of Down’s syndrome pregnancy changed over time?

• 71% increase in Down’s syndrome pregnancies (1989–2008)

• Likely driven by increasing maternal age

• Your note:

  • Mostly due to women having children later

What typically happens to Down’s syndrome pregnancies?

Majority end in:

• Miscarriage

• Pregnancy termination

Why are clinically observed trisomies considered the “tip of the iceberg”?

• Most aneuploid embryos fail before implantation

• Therefore never clinically recognised

• Only a small fraction progress to later stages

  • Very few reach a stage resembling foetal life

What is the lifecycle of the female germline?

When and how are female germ cells formed?

• Primordial germ cells form early (3–5 weeks gestation)

• Oocyte pool established before birth (~7 million mid-gestation)

• Finite supply — no new oocytes after birth

• Your notes:

  • First cells laid down = primordial germ cells

  • ~7 million halfway through gestation

  • If fetus is female → germ cells begin forming at 3–5 weeks

What happens to oocytes from fetal life to ovulation?

• Oocytes remain arrested in ovary (germinal vesicle stage)

• Stay there until stimulated for ovulation

• Resume meiosis before ovulation:

  • Complete meiosis I

  • Enter meiosis II

• Your notes:

  • Sit in ovary until ovulation

  • Sit in germinal vesicle stage until stimulated

What happens to oocytes during and after fertilisation?

• Meiosis II only completed if fertilisation occurs

• Fertilised egg → embryo → implantation

• Your notes:

  • Go most of the way through meiosis II but only finish if fertilised

  • Healthy embryo implants in uterus

What is meiosis?

• Specialised cell division producing haploid gametes from diploid cells

• Involves:

  • 1 round of DNA replication

  • 2 rounds of chromosome segregation

• Reduces chromosome number by half (“lessening”)

• Compared to mitosis:

  • Mitosis = alternating rounds of DNA replication and segregation

What happens during mitotic cell division?

• Replicated chromosomes → 2 sister chromatids

• Chromatids align on spindle

• Sister chromatids separate into daughter cells

• Outcome:

  • Cells retain 2 copies of each chromosome

What happens during meiotic cell division?

• Homologous chromosomes pair (bivalents)

• Meiotic recombination occurs

• Two divisions:

  • Meiosis I → separates homologues

  • Meiosis II → separates sister chromatids

• Outcome:

  • Haploid cells (1 copy of each chromosome)

How does meiosis differ between males and females?

• Males: 4 haploid sperm produced

• Females: only 1 viable oocyte (others discarded as polar bodies)

• Your notes:

  • Oocyte discards chromosomes to maintain large size

  • Early embryo has no blood supply → relies on stored resources

  • Unequal division occurs again in second meiotic division

How does the oocyte pool change across the lifespan?

• Oocyte stock established before birth

• Declines continuously with age (ovarian ageing)

• Vast majority of oocytes undergo atresia (die)

• Numbers:

  • Birth: ~1 million

  • Menopause (~45–55 yrs): <1,000

• Primordial follicles are recruited throughout life

Why does fertility decline with age despite IVF?

• Age-related fertility decline not rescued by IVF using own eggs

• Suggests problem lies with the oocyte (egg), not uterus

• Your notes:

  • Issue is the oocyte itself

  • Evidence from use of donor eggs

What does donor egg IVF tell us about female fertility decline?

• Using donor eggs from younger women:

  • IVF success rates remain high across ages

• Shows fertility decline is due to egg quality, not maternal environment

• Your notes:

  • Success rate stays high with donor eggs

  • Confirms age-related infertility = egg problem

How are ovarian ageing and aneuploidy related?

• Ovarian ageing = decline in number of oocytes

• Occurs alongside ↑ aneuploidy in oocytes

• Cause:

  • Chromosome segregation errors during meiosis

• Key idea:

  • Fewer eggs + lower quality with age

How are bivalent chromosomes held together during meiosis?

• Homologous chromosomes pair via meiotic recombination

• Form bivalents

• Stabilised by cohesin (Rec8-containing complexes)

• Cohesin holds sister chromatids together

Why does cohesion failure lead to aneuploidy with age?

• Cohesin is not replenished over time

• Weakens during long arrest in oocytes

• Leads to chromosome segregation errors

  • Sister chromatids must stay attached until meiosis II

  • Must be released at the correct stage

  • Errors in timing → aneuploidy

How do chromosomes attach to the spindle during meiosis I?

• Sister centromeres attach to microtubules from the same spindle pole (monopolar attachment)

• Bivalents stabilised by cohesin

• Ensures homologous chromosomes (not sisters) separate in meiosis I

What changes in chromosome attachment and cohesion during meiotic division?

• Cohesion must be removed stepwise during meiosis

• At division:

  • Chromosomes reorient → pulled to opposite poles

  • Cohesion broken between homologues

• Outcome:

  • One set lost in polar body, one retained in oocyte

• Cleavage must occur stepwise

• Cohesion breaking is tightly controlled

• Ensures correct chromosome segregation

What happens to cohesin during the first meiotic division (meiosis I)?

• Cohesin is removed from chromosome arms

• Allows homologous chromosomes to separate

• Cohesin at centromeres is preserved

• Your notes:

  • Removed from arms but kept at centromeres

  • Cohesion removal is highly specific

How is centromeric cohesin protected during meiosis I?

• Shugoshin (SGO1/SGO2) protects centromeric cohesin

• Recruits PP2A phosphatase

• Prevents cohesin (Rec8) from being cleaved by separase

• Your notes:

  • Protection depends on phosphorylation state

  • Centromeric cohesin cannot be recognised by separase

  • Ensures sister chromatids stay together until meiosis II

What is the role of centromeric cohesin in meiosis II?

• Enables bipolar attachment of sister centromeres

• Allows sister chromatids to attach to opposite spindle poles

• Ensures accurate segregation in meiosis II

What happens to centromeric cohesin before and during meiosis II?

• Shugoshin is removed/degraded between meiosis I and II

• Centromeric cohesin becomes “deprotected”

• Separase cleaves cohesin (Rec8)

• Sister chromatids finally separate

  • Shugoshin removal is key step between M1 and M2

What are the key steps controlling chromosome segregation in meiosis I?

• Bivalents stabilised by cohesin

• Monopolar attachment of sister centromeres

• Separase cleaves cohesin on chromosome arms

• Homologous chromosomes separate

What ensures correct chromosome segregation in meiosis II?

• SGO2 protects centromeric cohesin during meiosis I

• In meiosis II:

  • Bipolar attachment of sister chromatids

  • Shugoshin removed → cohesin deprotected

  • Separase cleaves centromeric cohesin

• Sister chromatids separate → haploid genomes formed

What meiotic errors occur in aged oocytes due to loss of centromeric cohesion?

What meiotic errors occur in aged oocytes due to loss of centromeric cohesion?

What molecular changes underlie age-related cohesion loss in oocytes?

• ↓ Cohesin (Rec8) levels

• ↓ Shugoshin (SGOL2) protection at centromeres

• Reduced recruitment of SGOL2

• Result:

  • Centromeric cohesion not maintained

  • ↑ risk of premature chromatid separation

• Your notes:

  • Less Rec8 and Shugoshin with age

  • Weakens protection of centromeric cohesion

How does centromeric cohesion loss relate to female age in human oocytes?

• Premature loss of centromeric cohesion ↑ with age

• In women >40:

  • 50–100% of oocytes show prematurely separated sister chromatids

• Consequence:

  • Major cause of aneuploidy

• Your note:

  • These prematurely separated chromatids are the ones that lead to errors

What is the role of the spindle assembly checkpoint (SAC) in oocyte meiosis?

• SAC ensures chromosomes are correctly attached to the spindle before separation

• Prevents chromosome missegregation

• Works via:

  • Inhibiting APC/C → separase inactive until ready

  • Once satisfied → separase activated → chromosomes separate

• Key point:

  • SAC is present and active in oocyte meiosis (like mitosis)

What are the “ticking clocks” of oocyte ageing?

• Three parallel but independent ageing processes:

  1. Oocyte depletion (loss of egg number)

  2. Cohesin depletion (chromosome instability)

  3. SAC decline (weaker error-checking)

• Ovarian ageing, Chromosomal ageing, Cell cycle ageing

• Occur in parallel but are mechanistically distinct