ERS23 Female Reproductive Cycle Flashcards
Meiosis
1 DNA replication + 2 divisions
- Meiosis 1: separation of Homologous chromosomes
- Meiosis 2: separation of Sister chromatids
4 phases:
- Prophase
- Preleptotene: **DNA synthesis (double chromosome number to 92)
- Leptotene: Nuclear size ↑, Chromosomes condense —> visible under microscope
- Zygotene: **Pairing of Homologous chromosomes at some point
- Pachytene: Pairing process move along entire chromosome, shortening + thickening, ***Crossing-over —> allow genetic materials of homologous chromosomes to exchange —> unique genetic composition
- Diplotene: formation of Chiasmata (site of crossing over) (chromosomes slightly apart but remain attached)
- Diakinesis: shortening and thickening of chromosome - Metaphase —> chromosomes alignment on metaphase plane, disappearance of nuclear membrane
- Anaphase —> separation of Homologous chromosomes
- Telophase —> formation of nuclear membrane of daughter cells
Meiosis 2:
- Metaphase
- Anaphase —> separation of Sister chromatids
- Telophase
Meiosis in ovary
Unique features:
- 2 interruptions
—> 1 after Diplotene 1 (Prophase 1): Chromosomes uncoil themselves to become thin again —> Dictyotene stage
—> 1 after Metaphase 2: Stage after ovulation
***Female primordial germ cells development
Female primordial germ cells (2C: 2 complement sets of chromosomes) derived from hindgut
—> Migrate to genital ridge
—> during migration + initial stage of ovarian development
—> Mitosis
—> germ cell number ↑
—> **Oogonia (2C) in ovaries
—> Oogonia undergo Meiosis (8-9 weeks, completed by 6 months)
—> **Primary oocyte (4C)
—> Arrest at Diplotene of Prophase 1
—> Growth of oocyte and follicle
—> Remain in ovarian follicle until puberty
—> **Follicular maturation: Follicle recruited for development in menstrual cycle
—> **Meiosis 1 resumed
—> Unequal cell division occurs in Meiosis of oocytes
—> 1 Large cell: Secondary oocyte (Mature egg: 2C) + 1 Small cell (1st polar body: residual body destined to degeneration)
—> Arrest again at Metaphase 2 upon **LH surge
—> Ovulation
—> Sperm entry and fertilisation
—> Resumption of Meiosis 2
—> large **Pronucleated oocyte (1C: Haploid) + ***2nd polar body
Note:
Prolonged Meiotic division ↑ chance of being affected by exogenous factors
—> ↑ chromosomal abnormalities with female age
—> Age-dependent ↑ in Trisomy 21 (Down syndrome), Trisomy 16, 18
Germ cell population in ovary
6 months:
Maximum no. of germ cells (7 million): ***ALL Oogonia becomes Primary oocyte
Time of birth:
1 million Primary oocyte in ovary (enough for use: 400 oocytes ovulated within female reproductive life)
—> Female germ cells in ovary die afterwards
—> Germ cell number ↓ with age
—> a few left after menopause
Summary of Oogenesis
Primordial germ cells: Mitosis (↑ number of PGC in ovaries)
Meiosis in female:
- start before birth —> ceiling on number of germ cells
- ends after fertilisation
- arrests at Prophase 1, Metaphase 2
- result in Unequal cell division (only 1 functional oocyte is produced after Meiosis)
Ovary
2 functions:
- Production of oocytes
- Hormone production (by ***Follicular cells surrounding oocytes)
Oocyte + Follicular cells —> Ovarian follicle (Basic functional unit of ovary)
Folliculogenesis:
Primordial follicle —> Developing follicle —> Mature follicle —> Ovulated follicle —> Corpus luteum
***Classification of Ovarian Follicle
4 types:
- Primordial (smallest)
- single Primary oocyte surrounded by single layer of flattened Follicular cells - Primary
- **↑ Oocyte size
- Oocyte surrounded by non-cellular layer **Zona pellucida
- proliferation of Follicular cells —> **multiple layers of Follicular cells surrounding oocyte
- Follicular cells —> **Granulosa cell + ***Theca cell - Secondary
- formation of **Antrum (fluid-filled cavity), **Cumulus cells
- **differentiation of Follicular cells into different cell types —> **produce Hormones - Tertiary / Graafian (largest)
- **resumption of Meiosis 1
- ↑ size of follicles (∵ **↑ Antrum size)
- Follicle bulge out just before ovulation at surface of ovary at a point—> Stigma
Structure of Primordial follicle
- Follicular cells (single layer) —> surround oocyte
- Basal lamina (最出)
- Primary oocyte
- Nucleus (Dictyotene)
- Nucleolus
- Cytoplasm of Follicle
***Follicular development
- Preantral phase (Primary follicle):
- **Independent of Gonadotropin
- Growth of follicle mainly due to **↑ Primary oocyte size
- Zona pellucida: non-cellular layer by Primary oocyte
- Granulosa cell + Theca cell (differentiated from Follicular cells)
- Granulosa cell: **Estrogen + **FSH receptors development
- Theca cell: **LH receptors development
—> by the end Follicle able to **respond to stimulation by Gonadotropins - Antral phase (Secondary follicle):
- **Dependent on Gonadotropin
- Growth mainly in **Follicular cells + **Antrum
- Granulosa cell + Theca cell —> **produce Estrogen + Androgen respectively
2 phenomena:
- Two-cells theory for Estrogen production
- Positive feedback of Estrogen production
- **Sustained FSH presence and high Estrogen
—> development of **LH receptor in Follicle - Preovulatory phase (Tertiary / Graafian follicle):
- **Dependent on LH surge —> **completion of Meiosis 1 —> **Secondary oocyte + 1st polar body
- **Meiosis 2 arrested at Metaphase 2
- Large ↑ in Antrum size
- **Progesterone production (由分泌Estrogen變左分泌Progesterone) by Granulosa cells a few hours after LH peak
- **Granulosa cells —> differentiated into **Corona radiata cells + **Cumulus cells —> surrounds oocyte and ovulated together with oocyte
- Cumulus cells: ovulated
- Corona radiata: specialised type of Cumulus cells around oocyte which gets ovulated - Ovulation
- Formation of Stigma (site on ovarian surface where Graafian follicle burst out)
- ↑ production of **Follicular fluid
- ↑ production of **Prostaglandins + **Proteolytic enzymes (to rupture follicle membrane)
- Rupture of follicle membrane
- **Oxytocin —> contraction of Follicular membrane —> push Secondary oocyte + Cumulus cell out of ovaries
- Secondary oocyte + Cumulus oophorus cells ovulated - Luteal phase
- Vascularisation of Granulosa layer
- Granulosa cells + Theca cells
—> transformed into Endocrine producing cells
—> Hypertrophy + Cell physiological changes
—> **Luteinisation
—> **Corpus luteum (80% Granulosa, 20% Theca)
—> **Estrogen + **Progesterone production
Growth of Follicle
Primary follicle:
- Main growth due to ↑ Oocyte size
Secondary Follicle:
- Main growth due to ↑ Follicle size (∵ formation of Antrum)
Structure of Primary follicle
- Primary oocyte
- **Zona pellucida
—> Granulosa cells send protrusions (microvilli) through Zona pellucida
—> touch Oocyte membrane
—> Interaction between Oocyte and Granulosa cells
—> **Granulosa cells regulate resumption of Meiosis 1 of oocytes
- Nucleus (Dictyotene)
- Nucleolus
- Cytoplasm of Follicle - Follicular cells
- **Granulosa cells —> multiple layers —> Zona granulosa (surrounding primary oocytes)
- **Theca cells - Basal lamina —> separate Granulosa cells / Theca cells
Structure of Secondary follicle
- ***Antrum (fluid-filled cavity in follicle)
- allow clinicians to observe growth of follicles by ultrasound - Follicular cells
- **Granulosa cells —> Endocrine cells (produce hormones)
- **Theca interna cells —> Endocrine cells (produce hormones)
- Theca extena cells —> Fibroblast-like
- Presence of blood vessels within Theca layer - Primary oocyte
- Zona pellucida
- Nucleus
- Nucleolus
- Cytoplasm of Follicle - Basal lamina
- Separate Granulosa cells / Theca interna cells
***Two-cells theory for Estrogen production in Secondary follicle
***LH receptor present in ***Theca cells LH bind to LH-R —> cAMP —> Androstenedione / ***Androgens (from cholesterol) —> diffuse through basal lamina —> becomes substrate for Granulosa cells
**FSH receptor present in **Granulosa cells
FSH bind to FSH-R
—> cAMP
—> stimulate Aromatase
—> convert Androstenedione to Estrogen
—> **Estrogen production
—> transported into bloodstream / go into Follicular fluid / act on Granulosa cells (∵ possess Estrogen receptor)
—> **stimulate Granulosa cells to proliferate more + enhance production of Estrogen receptors
—> +ve feedback
***Fate of Corpus luteum
No fertilisation
—> Luteolysis (Corpus luteum die) (10-12 days after ovulation)
—> Corpus albicans (regressed Corpus luteum)
—> ↓ production of Estrogen + Progesterone
—> allow next cohort of follicles to develop
Fertilisation
—> formation of embryo + placenta
—> Blastocyst stage
—> **Blastocyst produce HCG (Human chorionic gonadotropin) (also by placenta in first 3 months of gestations)
—> HCG function ~ LH
—> continues to “luteinise” Corpus luteum
—> **allow Corpus luteum to continue produce Estrogen + Progesterone
—> until Placenta itself can produce Estrogen + Progesterone
—> maintain lifespan of Corpus luteum for ***3 months after pregnancy
—> Luteolysis (Corpus luteum die) after 3 months
—> Corpus albicans (regressed Corpus luteum)
Reproductive cycle in females
- Follicular phase: 7-23 days
- Periovulatory period: 1-3 days
- Luteal phase: 14 days (relatively constant) —> important to estimate time of ovulation when day of menstruation is known
Total: 21-35 days (average 28 days)
Hormones in female reproduction
- GnRH (Hypothalamus)
- FSH, LH (Pituitary)
—> FSH: Maturation of follicles + LH-R expression
—> LH: Corpus luteum formation + Ovulation - Estradiol, Progesterone (Ovaries)
—> Estradiol: from Follicles, Corpus luteum
—> Progesterone: from Corpus luteum
—> -ve feedback to pituitary
***Hormonal pattern in female reproductive cycle
Day of menses: Day 1
Initial phase:
- FSH high (stimulate ↑ follicle size —> high Estrogen level)
—> ↓ with development
—> -ve feedback by Estrogen on Hypothalamus + Pituitary (only require **Low level of E2, Rapid onset)
- Estrogen ↑ (stimulate FSH, LH synthesis but **inhibit secretion —> accumulation of FSH, LH in pituitary)
Day 11-14 (Preovulatory phase):
- FSH ↑
—> High estrogen level become **stimulatory to synthesis + secretion —> +ve feedback —> FSH surge (一野爆出黎)
- LH ↑
—> High estrogen level become **stimulatory to synthesis + secretion —> +ve feedback —> ***LH surge (一野爆出黎) —> Ovulation + Corpus luteum
—> Luteinisation of Granulosa cells to produce Low level of Progesterone (a few hrs after LH surge) (Luteinisation starts before ovulation) —> ↑ pituitary sensitivity to GnRH
- Estrogen ↑ (2-3 days: induce ovulation + Luteinisation of Granulosa/Theca cells of follicular wall to become Corpus luteum)
After Day 14 (Luteal phase, formation of Corpus luteum —> Estrogen + Progesterone —> -ve feedback to FSH, LH, GnRH):
- FSH low
- LH low
- Estrogen high
- Progesterone high
Late Luteal phase (no fertilisation —> degeneration of Corpus luteum):
- FSH ↑ —> stimulate growth of next cohort of follicles
- Estrogen ↓
- Progesterone ↓
Follicular phase summary
GnRH ↑ FSH/LH release —> FSH ↑ growth of follicles —> Granulosa + Thecal cells produce Estrogen (↑ Estrogen) —> Estrogen -ve feedback: 1. ↓ FSH/LH release from pituitary 2. ↓ GnRH release from Hypothalamus 3. ***↑ FSH/LH synthesis
Follicular maturation
- Recruitment phase (1-3 days)
- a cohort of ***preantral follicles depart from resting pool and begin to grow (development of multiple follicles)
- Preantral follicle not responsive to Gonadotropin —> can develop / undergo atresia - Selection phase (5-11 days)
- one member from cohort becomes Dominant follicle
—> continue to develop to preovulatory follicles (mechanism unclear, maybe follicle with highest sensitivity to FSH)
(Assisted reproduction treatment: give high dose FSH —> stimulate more follicle to develop) - Dominance phase (13-15 days)
- Dominant follicle ovulated eventually
- other “un-ovulated” follicles die via Atresia (Atretic follicle)
Ovulation phase summary
High estrogen for 2-3 days (***+ve feedback)
- ↑ ***release and synthesis of FSH/LH
- ↑ ***release of GnRH
- ↑ pituitary sensitivity to GnRH
Low progesterone potentiates effect of Estrogen-induced LH surge
- ↑ pituitary sensitivity to GnRH
Luteal phase summary
Early / Mid luteal phase (-ve feedback again)
- High Estrogen + Progesterone ↓ GnRH release
- ***High Progesterone blocks Estrogen actions
Late luteal phase
- Luteolysis —> Estrogen, Progesterone ↓ —> removal of inhibition —> FSH ↑
Action of Estrogen from dominant follicle
- Inhibit growth of cohort follicles
- Enhance sperm transport through cervical mucus
- Enhance transport of ovum in oviduct
- Prime endometrial response for progesterone induced secretion (Prepare endometrium for implantation)
- Prime GnRH action on LH secretion for LH surge
Action of Progesterone from Corpus luteum
- Ovulation (potentiates effect of Estrogen-induced LH surge)
- Uterine secretion in preparation for implantation (make endometrium more secretory)
- Development of embryo (stimulates Decidualization of endometrium to provide support for development of embryo)
Endometrial changes during menstrual cycle
- Proliferative phase
- Estrogen stimulate ***proliferation of endometrium (during Initial development of follicle)
- early proliferative phase: only simple glandular endometrial glands
- late proliferative phase: glands become bigger, start to see mitotic figures - Secretory phase
- after ovulation
—> Progesterone from Corpus luteum stimulate **secretory events of uterine glands + **development of endometrium
—> receptive to implanting embryo
- early secretory phase: within glandular epithelium, can see vacuole-like structures at the base of glands (contains secretions of glandular epithelium —> released into glandular lumen)
- late secretory phase: lumen become much bigger with secretions
Basal body temperature changes
- Determine ovulation
- Increase in body temp after ovulation by Progesterone (slight delay)
—> Egg already ovulated before rise in body temp (not accurate in contraception)
Cervical mucus changes
Ferning:
- Crystal formed by cervical mucus at time of ovulation
- mucus to dry —> ferning
- Estrogen action —> composition in cervical mucus changes
Score of ferning pattern:
- ***high around ovulation (ferning —> fluid)
- change in cervical mucus composition ***allow sperm to penetrate through mucus —> fluid instead of viscous
Summary
Hormone:
- FSH, LH changes
- E2, P changes
Ovary:
- Follicular phase
(- Ovulation phase)
- Luteal phase
Follicle:
- Preantral phase (85 days) (i.e. Primary follicle) (throughout reproductive cycle, ***Independent of Gonadotropin, follicle with high enough sensitivity to FSH develop into Antral phase)
- Antral phase (8-12 days) (i.e. Secondary follicle)
- Preovulatory phase (37 hrs) (i.e. Tertiary / Graafian follicle)
- Corpus luteum phase (14 days)
Endometrium:
- Proliferative phase
- Secretory phase
Detection of ovulation
- ***Menstrual cycles (if regular cycles)
- Basal body temperature (after ovulation, cannot be used to pinpoint exact time of ovulation)
- Urinary ***LH level (Ovulation specific, but difficult to catch 1/2 day of LH surge)
- Blood (***Progesterone level, only produced by Corpus luteum, occur after ovulation)
- Ultrasound (Development of antral follicle —> ***disappearance of Antral follicle —> indicate time of ovulation —> but require daily ultrasound)