M6(6) Oogenesis, Follicle Development, Ovarian Cycle, Female HPG Axis

Oogenesis

The process of producing female gametes (ova/ovum)

• Occurs in ovaries and begins before birth, only finishes if fertilization happens

Oogonia

Diploid germ cells in females

Oogenesis Stages

1. Fetal Stage

2. At Birth

3. From Puberty

4. Ovulation

5. Fertilization

6. No Fertilization

Fetal Stage

Before Birth

1. Oogonia divide by mitosis

• Becomes primary oocytes

2. Primary oocyte begins meiosis I

• Arrested in prophase I

At Birth

All primary oocytes arrest at prophase I

• Originally ~7 million → ~2 million remain in the cortical region of the ovary

From Puberty

Only the primary oocyte in the dominant follicle resumes meiosis I

• Produces two distinctly sized haploid cells

  • First Polar Body

  • Secondary Oocyte

First Polar Body

A smaller haploid cell that MAY continue development, undergoing meiosis II

• Produces two even smaller polar bodies from meiosis II

FPB or the smaller PBs that it generates will degenerate

Secondary Oocyte

A larger haploid cell that continues development, undergoing meiosis II

• Arrested in metaphase II

• Released from ovary (ovulation) while arrested

Secondary Oocyte and No Fertilization

If the ovulated secondary oocyte does not get penetrated by sperm (i.e. fertilization does not occur)

• Then the oocyte deteriorates

Secondary Oocyte and Fertilization

If the ovulated secondary oocyte DOES get penetrated by sperm (i.e. fertilization DOES occur)

• Then the oocyte completes meiosis II

• Yields one large ovum and a tiny second polar body

Ovarian Follicle

Functional unit of the ovary; Responsible for supporting oocyte development and hormone production

• Consists of primary oocyte surrounded by supporting cells

Follicular Cell Terminology

Surrounding cells (follicular cell names differ):

• Pre-granulosa cells → single layer of cells present

• Granulosa cells → more than one layer of cells present

Ovarian Follicle Stages

Different stages of maturation distinguished by size/structure

• Primordial Follicle

• Primary Follicle

• Secondary Follicle

• Vesicular/Antral/Tertiary Follicle

Primordial Follicle

• Contains primary oocyte

• Surrounded by one layer of squamous cells (pre-granulosa)

Primary Follicle

• Contains primary oocyte

• Surrounding cells become cuboidal pre-granulosa cells

Secondary follicle

• Contains primary oocyte

• Multiple layers of granulosa cells

• No fluid cavity yet

Vesicular Follicle

• Contains primary oocyte

• Large fluid-filled cavity = antrum

• Just before ovulation, the primary oocyte resumes meiosis and becomes a secondary oocyte

Ovarian Follicle Development Steps

1. Primordial to Primary Follicle

2. Primary to Secondary Follicle

3. Secondary to Vesicular Follicle

Primordial to Primary Follicle

1. Primordial follicle is recruited

2. Squamous cells surrounding the primary oocyte grow and become cuboidal cell

3. Oocyte enlarges

• At this point primordial is now primary

4. At the same time, oocyte secretes glycoprotein-rich substance forming a transparent extracellular layer called zone pellucida

5. Zone pellucida encapsulates oocyte

Primary to Secondary Follicle

6. Pre-granulosa cells proliferate, forming stratified cuboidal epithelium (turning into granulosa cells)

• At this point, primary is now secondary

7. Granulosa cells connected to oocyte via gap junctions

• Ions, metabolites, signalling molecules can pass thru

• From this point on, oocyte and granulosa cells guide one another’s development

8. As follicle grows, a layer of connective tissue and epithelial cells condenses around the follicle, forming the theca folliculi

9. Some thecal cells secrete hormones in response to LH

Secondary to Vesicular Follicle

10. Secondary follicle stage ends when clear liquid accumulates between the granulosa cells

• At this point, secondary is now early vesicular follicle

11. Once 6-7 layers of granulosa cells are present, fluid coalesces to form an antrum (fluid-filled cavity)

• At this point, the antral phase begins

12. Antrum continues to expand with fluid until it almost surrounds the oocyte and its surrounding capsule of granulosa cells (now called a corona radiata)

• Bulges from external ovarian surface like a pimple (usually occurs right before ovulation)

13. After the oocyte + corona radiata is ejected from the follicle, the ruptured follicle transforms into a glandular structure called the corpus luteum (yellow body)

Ovarian Cycle

The monthly sequence of events that prepares and releases an egg, split into 2 phases

1. Follicular Phase

2. Luteal Phase

Follicular Phase

Starts on day 1 of menstruation (days 1-14)

1. Near the end of the previous cycle, FSH rises → rescuing a group of follicles from atresia

2. Multiple vesicular follicles begin developing

3. One becomes more sensitive to FSH (dominant follicle)

4. Mid-phase, FSH levels drop and the most FSH-sensitive follicle outcompetes the others

5. The primary oocyte contained within the dominant follicle completes meiosis I (forming the secondary oocyte + first polar body)

Ovulation

6. Estrogens, produced by the follicle, continue to rise

7. At a certain point estrogen switches from negative to positive feedback → triggers LH surge

8. Follicle ruptures → releases secondary oocyte surrounded by corona radiata into peritoneal cavity

9. Captured by fimbrae

Luteal Phase

Begins after ovulation (days 14-28)

10. Ruptured follicle collapses and the antrum fills with clotted blood (becomes corpus hemorrhagicum which is eventually absorbed)

11. Remaining granulosa cells enlarge and with the internal theca cells, form the corpus luteum

12. If the oocyte is not fertilized, the corpus luteum degenerates after about 10 days (and all that remains is a scar called corpus albicans, hormones drop → menstruation)

13. If the oocyte is fertilized, the corpus luteum continues hormone production until placenta takes over (~3 months)

Multiple Ovulations

~1–2% of cycles → multiple ovulations → can lead to multiple births

• This phenomenon increases with age

Mittelschmerz

Twinge of pain that occurs during ovulation

• Direct cause is not known but possible reasons include:

  • Stretching of ovarian wall

  • Irritation from fluid/blood after rupture

Establishing the Ovarian Cycle

1. Childhood

2. Approaching Puberty

3. Early Puberty

4. Menarche

5. Full Maturation

Childhood

Ovaries grow and secrete small amounts of estrogens

• Inhibits hypothalamic release of GnRH

• Result: Very low FSH + LH → no ovarian cycle

Approaching Puberty

Hypothalamus becomes less sensitive to estrogen

• Estrogen is less effective at inhibiting the hypothalamus

• Result: Promotes GnRH → Promotes FSH + LH → (NO OVULATION YET)

Leptin (from fat tissue) linked to onset of puberty, signaling the body has enough energy stores

Early Puberty

FSH + LH levels increase over ~4 years

• During this time, girls cannot ovulate or become pregnant

Adult Cyclic Pattern

Eventually, the adult cyclic pattern is achieved and hormonal patterns stabilize

• Woman’s first menstrual period referred to as menarche

• Usually, it’s not until the third year post menarche that cycles become regular and are all ovulatory

Female HPG Axis Steps

1. Hypothalamus releases GnRH → stimulates anterior pituitary release of FSH + LH

2. FSH and LH stimulates follicles to grow and secrete sex hormones

• FSH → granulosa cells → release estrogens

• LH → theca cells → release androgens → converted to estrogens by granulosa cells

3. Estrogen levels reach a critical threshold, switching from negative → positive feedback on hypothalamus + anterior pituitary

4. LH surge happens and triggers ovulation and formation of corpus luteum

5. Negative feedback (progesterone + estrogen + inhibin) inhibit GnRH, FSH, LH

• Prevents new follicles from developing and second ovulation from occurring