Oogenesis Lecture Vocabulary

Oogenesis Learning Objectives

• Describe which parts of oogenesis occur before birth and which occur during adulthood.
  • When does the oocyte carry out mitosis, meiosis I, and meiosis II?
• Explain how the number of primordial follicles changes over the lifespan.
• Summarize the source and function of the major hormones regulating the menstrual cycle.
  • When do the levels of each hormone peak/decline?
• Describe the events of the menstrual cycle in order, beginning with menstruation.
  • What happens during the menstrual, proliferative, and secretory phases?
• Determine which stage of development a follicle & its oocyte is in based on the structure and number of the surrounding follicle cells.
• Identify the two types of follicle cells and what they do.
• Explain how the number of active follicles changes during the menstrual cycle.
  • What signals do the follicles respond to?
• Describe the changes to the endometrium and cervix in the menstrual cycle.
  • How do these changes support a potential pregnancy?
• What triggers ovulation?
  • What is released from the ovary during ovulation?
• Explain how only one mature gamete (egg) is produced from a primary oocyte.
  • Why aren't 4 gametes generated as in spermatogenesis?
• Explain the role of the corpus luteum in supporting a potential pregnancy.
  • Where does the corpus luteum come from?
• Compare and contrast oogenesis and spermatogenesis.
• Explain how aging affects ovarian function.
• Describe the causes and effects of Polycystic Ovarian Syndrome and Primary Ovarian Insufficiency on the body.

Overview of Oogenesis and the Menstrual Cycle

• Oogenesis involves changes to the ovary, follicle cells, and uterus.
• Oogenesis begins in fetal development, then undergoes a long dormant period, then resumes in puberty.
• A set of cyclical hormones regulate the menstrual cycle.
• During the menstrual cycle, a cohort of 5-12 oocytes and their surrounding follicle cells begin maturing. One follicle and its egg will complete the maturation process and be ovulated.
• The endometrium of the uterus changes during the menstrual cycle to prepare to receive the egg if it is fertilized.

Fetal Development and Oogenesis

• Oogenesis begins in fetal development.
• Primordial germ cells (PGCs) in females migrate from the yolk sac into the genital ridge, as in spermatogenesis.
• PGCs undergo many rounds of mitosis during embryonic development and differentiate into oogonia by month 3 of fetal development.
• Oogonia enter the prophase of Meiosis I where they stall as primary oocytes by month 5.
• Follicle cells surrounding the oocyte produce meiotic inhibitory factors (MIF) that block the progression of meiosis.
  • These factors generate high levels of cAMP in the oocyte that blocks meiosis.
• The nucleus of the dormant primary oocyte swells and is called a germinal vesicle.
  • This protects the DNA during the long meiotic arrest.

Primordial Follicles

• Primordial follicles are the dormant stage of oocytes.
• In fetal development, each oocyte is protected by a single squamous layer of epithelial follicle cells.
  • This structure is called a primordial follicle and remains dormant until puberty.
• Oocyte + its surrounding nurse cells = follicle.
• By 5 months, when all oogonia have converted to primary oocytes stalled in Meiosis I, the number of primordial follicles peaks at approximately 7 million.
• Follicles undergo selective degeneration throughout the lifespan.
• At birth, approximately 700,000-2 million primordial follicles remain.
• At puberty: approximately 400,000 remain.

Hormonal Control of the Menstrual Cycle

• At puberty, females begin a monthly cycle of hormones called the menstrual cycle.
• The menstrual cycle lasts approximately 28 days and includes:
  • Cyclical release of hormones
  • Complete maturation of a single oocyte and its surrounding follicle
  • Proliferation of the uterine endometrium
  • Ovulation - oocyte is released from the ovary
  • Development of the follicle into the corpus luteum
  • Shedding of the endometrium and degradation of the corpus luteum (unless a fertilized egg implants in the uterus)
• There are 3 phases of the menstrual cycle, and it begins with menstruation (bleeding).
  • Menstrual phase – Days 0-5
  • Proliferative phase – Days 5-14
  • Secretory phase – Days 14-28
  • Ovulation is on approximately Day 14

Hormones Regulating the Menstrual Cycle

• Beginning at puberty in females, there is a cycling of hormones produced by 3 tissues:
  • Hypothalamus
    • Produces gonadotropin-releasing hormones (GnRHs) in pulsing waves/surges (GnRH release is steady in males).
    • GnRHs induce FSH and LH secretion by the pituitary.
  • Pituitary
    • Produces follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (many functions).
    • FSH regulates folliculogenesis in the ovary.
    • LH regulates the proliferation of the uterine endometrium.
    • Both control estrogen production in the ovary.
  • Ovary
    • Produces estrogen (E) and progesterone (P).
    • E and P regulate the development of the endometrium.
• What triggers puberty?
  • Not fully understood, but linked to:
    • Leptin levels (fat stores)
    • Genetics (polygenic)
    • Circadian rhythms
  • Age of onset has decreased, primarily due to improvements in nutrition and socioeconomic conditions.

Menstrual Phase (Days 0-5)

• Day 1 = First day of bleeding.
• Shedding of the endometrium from the previous cycle.
• 5-12 primordial follicles resume development and convert into primary follicles.
  • Primary follicles = surrounded by a single layer of cuboidal follicle cells.
  • This change is NOT controlled by GnRH or FSH.
• Primary follicle cells secrete a thin layer of glycoprotein between the follicle cells & oocyte called the zona pellucida.
  • Extensions from follicle cells extend through ZP and connect to oocyte.
• GnRH pulses increase in frequency, causing FSH levels to increase.

Proliferative Phase (Days 5-14)

• Also known as the follicular phase.
• By day 5, the cohort of selected primary follicles respond to FSH & continue developing.
• Maturing follicles accumulate more layers of follicle cells and produce more estrogen as they grow.
  • Primordial follicle = single layer squamous cells
  • Primary follicle = single layer of cuboidal cells
  • Secondary follicle = two or more layers of follicle cells but no antrum
  • Antral follicle = antrum of any size but not Graafian
  • Graafian follicle = fully developed follicle, large antrum with cumulus oophorus

Follicle Cell Layers

• Maturing follicles develop two functional layers of cells:
  • Granulosa cells - produce estrogen
  • Thecal cells – produce testosterone
• Granulosa cells convert testosterone produced by the thecal cells into estrogen by the enzyme aromatase.
• FSH promotes aromatase expression.

Antrum Development and Follicle Selection

• The follicle cells also begin secreting fluid within the layers of follicle cells, creating a pocket called an antrum.
• The antrum continues to grow through the proliferative phase.
• The follicle cohort compete with one another to become the dominant follicle – the follicle growing the fastest.
• Elevated estrogen begins to inhibit FSH (negative feedback loop).
  • The dominant follicle has more FSH receptors and can continue to grow, while smaller follicles stop growing and eventually degenerate.

Endometrial Changes During Proliferative Phase

• Estrogen produced by maturing follicles causes the uterine endometrium to proliferate.
• Uterine glands proliferate – will be used to secrete hormones and histiotroph (uterine milk) in the event of implantation.
• Histiotroph nourishes the early embryo through diffusion up to week 10 of development and placental maturation.
• Spiral arteries begin to extend into the growing endometrium.

Ovulation Trigger

• Estrogen secretion increases greatly around day 10, causing a burst of GnRH, which causes a rise of FSH and LH (ovulatory surge).
• The surge in LH triggers ovulation.
• Inhibin B secreted by granulosa cells inhibits FSH and prevents it from rising as dramatically as LH. This prevents maturation of non-dominant follicles.
• LH surge stimulates the primary oocyte of the mature Graafian follicle to resume meiosis, and the germinal vesicle (nucleus) breaks down.

Meiosis I Completion

• The metaphase plate of meiosis I forms at the edge of the cell.
• At telophase one daughter cell contains all the cytoplasm while the other daughter cell is tiny.
• The larger cell is the secondary oocyte and the smaller cell is the 1st polar body.
  • This process conserves the important cytoplasm of the oocyte.
• The secondary oocyte begins meiosis II but stalls again in the second meiotic metaphase hours before ovulation.
• Ovulation occurs approximately 36 hours after the ovulatory surge.

Ovulation (Day 14)

• Ovulation occurs on approximately Day 14.
• The oocyte is extruded from the surface of the ovary when the dominant follicle wall ruptures.
• The oocyte is released with a mass of cumulus oophorus (follicle) cells that travel with it.
• The fimbriae of the oviduct collect the oocyte/cumulus mass from the ovary surface, and it begins traveling down the oviduct (Fallopian tube).

Secretory Phase (Days 14-28)

• Also known as the luteal phase.
• After ovulation, granulosa and thecal cells of the ruptured dominant follicle proliferate and convert to luteal cells, forming a temporary endocrine organ called the corpus luteum.
• The corpus luteum secretes high levels of progesterone and moderate levels of estrogen.
  • This combination promotes further growth and maintenance of the endometrium.
• If there is no implantation, the corpus luteum will degenerate after approximately 14 days, converting to a scar-like tissue called the corpus albicans.
• If fertilization occurs, the embryo secretes the hormone chorionic gonadotropin (hCG), which maintains the corpus luteum.
• Falling progesterone levels trigger shedding of the endometrium and start of a new cycle.

Endometrial Changes During Secretory Phase

• The endometrium thickens and develops dramatically more uterine glands and spiral arteries – tightly coiled blood vessels that supply the endometrium.
• Spiral arteries are remodeled during pregnancy and contribute to the placenta.

Comparison of Oogenesis and Spermatogenesis

Cervical Changes During the Menstrual Cycle

• The cervix is the lowest part of the uterus that connects the uterus to the vagina.
• The position of the cervix rises around ovulation.
• The entrance to the cervix (os) is more open during ovulation and menstruation.
• The cervix secretes a complex combination of fluids called cervical mucus.
  • The consistency of cervical mucus changes through the cycle.
  • Around ovulation, a thin, slippery mucus is secreted that aids in sperm transport through the cervix.

Oogenesis and Aging

• Reproductive aging includes a decline in both the quality and quantity of gametes.
• Varies by individual, but fertility declines throughout the reproductive years until menopause, typically around age 50.
• AMH (anti-mullerian hormone) levels are used to measure ovarian reserve.
  • AMH is synthesized by granulosa cells of primary-early antral follicles.
• Number of primordial follicles:
  • Fetus: 7 \text{million}
  • Birth: 1-2 \text{million}
  • Puberty: 400,000
  • Age 37: 25,000
  • Menopause: 1000
• The level of AMH is used to estimate functional ovarian reserve – how many follicles are activating in each cycle.
  • AMH can predict the number of follicles, but not their quality.

Chromosomal Abnormalities and Aging

• As oocytes age, the rate of chromosomal abnormalities increases.
• Aneuploidy = abnormal chromosome number. Most aneuploidies are fatal, except for missing or extra sex chromosomes and trisomy of chromosome 21 (Down Syndrome).
• Individuals with trisomy 18 (Edward syndrome), and trisomy 13 (Patau syndrome) may rarely survive.
• Non-disjunction during meiosis I or II is the primary cause of aneuploidies.
• Some aneuploidies also develop from a mistake in mitosis during early development, resulting in mosaicism – some body cells are affected, others are not.
• Maternal age and incidence of Trisomy 21 (Down Syndrome):
  • 20 years: 1:2000
  • 25 years: 1:1200
  • 30 years: 1:900
  • 35 years: 1:350
  • 40 years: 1:100
  • 45 years: 1:30

Cohesin Degradation and Aging

• During the meiotic arrests, the protein cohesin holds the kinetochores of sister chromatids together, keeping them organized.
• Cohesin and its stabilizer protein SGO2 degrade over time in an age-related manner.
• Kinetochore distance increases with oocyte age.
  • This increases the probability of unequal segregation of chromatids during meiosis.

Polycystic Ovarian Syndrome (PCOS)

• PCOS is a hormonal disruption of the female reproductive system, affecting 5-20% of women.
• Common symptoms include infertility, absent or irregular menstrual cycles, enlarged/polycystic ovaries, obesity, and excess hair growth.
• In most cases, ovaries contain numerous follicles arrested in the antral follicle state, creating ‘cysts’.
• Elevated testosterone levels are created by thecal cells of the arrested follicles.
• Elevated inhibin levels suppress FSH, skewing the LH/FSH ratio to high LH.
• Low FSH suppresses aromatase in granulosa cells, preventing them from converting testosterone to estrogen.
• Multi-system disorder that is not fully understood.
• Treatments include hormonal birth control, weight management.

Primary Ovarian Insufficiency (POI)

• Early depletion or dysfunction of follicles, before 40 years of age.
• Approximately 50 different genes have been associated with POI. Most function in meiosis, DNA repair, or ovarian function.
  • The most common genetic cause is a variant mutation of FMR1 (more severe mutations cause Fragile X syndrome).
• Other causes include gonadal dysgenesis, Turner syndrome, and chemotherapy/radiation treatment.
• The primary symptom is infrequent or absent menstruation.
• Ovarian hormones are broadly important for female health, not just reproduction.
  • Individuals with POI, especially adolescents, are treated with hormone replacement therapy.
  • Estrogen – bone and cardiovascular health; secondary sex trait development.
  • Progesterone – given for 1.5 weeks per month. Withdrawal of progesterone triggers ‘withdrawal bleeding,’ similar to menstruation, and prevents overgrowth of the endometrium, and the risk of endometrial cancer.
• 5-10% of women with POI have spontaneous pregnancies.