Menstrual Cycle - Follicular and Luteal Phase Flashcards
Why is pulsatile GnRH important?
− The pulses can be released in different frequencies, and this is important as it has an impact on which gonadotrophin is released
− Pulses are also important for keeping the receptor on the cell surface – if stimulation were continuous, the receptor would be downregulated and internalized.
What subunits do FSH and LH consist of?
- Dimeric glycoproteins – alpha and beta subunit
* Alpha subunits are identify in both, the beta subunit confers hormone specificity
Describe the acidic forms of FSH and LH?
Decreased receptor binding
Decreased bioactivity
Longer half life
- -> might be involved in the early follicular phase.
- -> seems to be present more in women who have gone through h menopause
Describe the basic form of FSH and LH?
More bioactive
Shorter half life
- -> may be involved in the late follicular phase, when we need to select the dominant follicle.
- -> More prevalent in women of reproductive age.
Describe the LH and FSH receptors
• GPCRs present on somatic cells in the ovarian follicles
• Generally coupled to Gas
− Activates adenylate cyclase which causes the conversion of ATP to cAMP
− cAMP activates PKA
− PKA phosphorylates and activates Arg-arg-X-ser/thr-X motifs in proteins
− These proteins can be enzymes involved in steroidogenesis
What pulses stimulate FSH?
Slow GnRH pulses - 1 every 2 to 3 hours
What pulses stimulate LH?
Fast GnRH pulses - more than 1 pulse an hour
How is FSH packaged within the cell?
Very little storage -released constitutively
How is LH packaged within the cell?
In electron dense granules, in association with the storage protein secretogranin.
Describe follicular development from germ cells to the primordial follicle
• Begins before the female is born → begins before birth, accelerates at puberty and ends at menopause.
- During week 4 of gestation, primordial germ cells migrate form the yolk sac to the fetal ovary and differentiate into oogonia.
- Mitosis occurs, but there is incomplete cytokinesis – leaves interconnected cells known as germ cell cysts/nests.
- Many germ cell cysts are lost by apoptosis, but between the 3rd and 7th month of gestation, they prepare to undergo meiosis – but become arrested in prophase I → this is the primary oocyte.
- The intracellular bridges break down, and you get enclosure of a single oocyte within a single layer of somatic cells – granulosa cells → This gives you the primordial follicle.
− It is thought around the time of birth, a female will have around 1 million primordial follicles
− they stay in arrested prophase I until they enter puberty
− environmental contaminants may results in a follicle that has two oocytes, not one. This is recognized as abnormal, and is destroyed. This has an effect on the reproductive lifespan of the individual.
White et al, 2010
The original dogma has always been that mitotic proliferation of oogonia is restricted to fetal life, but this is now being challenged due to the discovery of oogonial stem cells in the ovary:
• White et al, 2010:
• Studies have independently shown that mouse OSCs can be isolated form adult ovaries for long-term propagation in vitro, and for generation of fertilisation competent eggs in vivo afer intraovarian transplant.
• Other work has reported that de novo oocyte formation in adult mouse ovaries can be stimulated by small molecule inhibitors of histone deacetylases
• The potential clinical relevance of these findings with mice is unclear because of a lack of definitive evidence that ovaries of reproductive-age women contain a comparable population of oocyte-producing germline cells that match the characteristic features of mouse OSCs.
• Method below describes a way of purifying viable OSCs from adult mouse and human ovary tissue:
− Isolated cells expressing DDX4 from the human adult ovary (germ cell specific RNA helicase)
− Labelled them with GFP
− Introduced these cells to human ovary biopsies
− Found to be numerous GFP positive cells throughout the tissue. and these formed aggregates that look similar to follicles.
− Put this biopsies into SCID mice → GFP labeled cells look to be forming primordial follicles
➢ This work shows you can get follicles from mitotically active germ cells present in the adult ovary
• Could have a huge impact on ART in older women
Describe a primordial follicle
- Primary oocytes are located in the outer portion of the cortex
- A single squamous layer of follicle cells surrounds each primary oocyte, forming a primordial follicle
Describe a primary follicle
- Primordial follicles are activated to form primary follicles
- Follicular cells enlarge, forming several layers of cells around the growing primary oocyte → granulosa cells.
- Microvilli from the surrounding follicular cells intermingle with microvilla on the surface of the oocyte, forming the zona pellucida → the glycoprotein region that sperm need to penetrate.
- The microvilli increase the surface area for transfer of materials from the granulosa cells to the oocyte
Describe a secondary follicle
• Only a few primary follicles mature further
• The wall of the follicle thickens, and the deeper follicular cells secrete follicular fluid which accumulates in small pockets
• This pockets expand and separate the inner and outer layer of the follicle.
• Adjacent cells form a layer of thecal cells (contaiing LH receptors):
− Theca interna → sex steroid synthesis
− Theca externa → structural support
What are oocyte secreted factors, and what is their role?
Oocyte secreted factors (paracrine factors)
• GDF9 (stimulatory)– absence causes sterility
• BMP 15 (stimulatory) – absence causes sterility
• FOXO (inhibitory)– inhibit PI3K/AKT signaling until de-depression by Kit
These bind to cell surface ser/thr kinases and activate Smad signaling molecules. This results in translocation to the nucleus, where they act as transcription factors
OSFs regulate granulosa cell: • Proliferation and differentiation • matrix production (important after ovulation, as it says with the ovulated oocyte, allowing it to migrate down the fallopian tube) • Estradiol production • Metabolism
