Physio Flashcards
- The menstrual cycle is composed of both the ovarian and uterine cycle.
- The ovarian cycle is divided by ovulation into the follicular phase and the luteal phase.
What is the uterine cycle divided into?
Proliferative phase and Secretory phase
note: ovulation causes the transition from one phase to the next in both the uterus and ovary
The arcuate nucleus stimulates GnRH release. Which form of GnRH is the physiological relevant form?
What is the major control mechanism for release of GnRH?
GnRH-1 Ultradian cycle (28 days)
(also: Estradiol, leptin, NPY, Norepi, circadian clock)
What effect do these have on GnRH? B-endorphin GABA Dopamine Estradiol
Inhibitory
TQ GnRH is released in a pulsatile manner. In what phases do the 2 different pulse cycles occur? What are the pulse rates? What are the hormones that are released?
Follicular/proliferative phase:
- Early in cycle to ovulation
- Every 90-100 min, promoting FSH
Luteal/secretory phase:
- After ovulation
- Every 3-5 hours, promoting LH release
The GnRH receptor (2) is expressed on gonadotropes in the ant. pituitary.
GnRH-R1: Gq11R»>incr Ca intracellularly
What is GnRH-R2 MOA?
Transcription and translation of genes coding for FSH and LH
- FSH and LH are considered glycoproteins of the ant. pituitary. Therefore, they both have an alpha-subunit. However, each has their own specific B-subunit. Each has a distinct Gs coupled receptor–>cAMP–>PKA
- What accounts for their differences in HL? What are each of their half lives?
FSH: 170 min (greater due to incr glycosylation)
LH: 60 min
They glycosylated which leads to differences in their HL.
Drive the developing follicles to produce steroid hormones estrogen and progesterone, as well as androgens.
FSH and LH
Predominates in the follicular/proliferative phase and contributes to ovulation.
Estrogen
What are the steps of estrogen production? (FSH)
1) Thecal cells convert cholesterol to androstenedione.
2) Androstenedione is transported to the granulosa cells
3) Granulosa cells have aromatase, which converts Androstenedione–>Estradiol
TQ
- There are 2 estrogen receptors (alpha and beta) produced by alternative splicing.
- ER are members of the nuclear receptor family (pass through membrane–>nucleus).
- 2 activation factors, a DNA binding domain, and a ligand binding domain
Which activation factor domain is associated with the ligand binding domain?
AF2
AF1 is NOT assoc. with binding…estrogen–>AF2–>effects!
The ligand binding domain of estrogen R is very large. What is the result of this?
A number of loosely related structures can fit into the receptor (agonists/antagonists).
Ex: Tamoxifen: long side chain prevents change in conformation of receptor, preventing activation and binding to DNA
How does estrogen act through AF2?
Steroid into nucleus>> Binds to ER>> Dimerizes with another E/ER complex>> Activation factors + DNA binding region interacts with DNA>> Alters transcription
TQ
How does estrogen act through AF1?
AF1 is on the cell membrane so estrogen acts as a second messenger system (Gs)
Why are exogenous agonists and antagonists often classified as partial/mixed? AKA they may act as an agonist in some functions but an antagonist in others.
Flexibility of the estrogen receptor due to its large ligand binding domain and the 2 different types of receptors.
Predominates in the luteal/secretory phase and prepares the body for pregnancy
Progesterone
What are the steps of progesterone production? (LH)
1) Thecal cells convert cholesterol to androstenedione and pregnenolone
2) Androstenedione and pregnenolone are transported to the granulosa cells
3) Granulosa cells respond to both LH/FSH convert androstenedione to progesterone (pulses of 3-5 hrs)
- There are 2 progesterone receptors (A and B form)
- It has 2 activation factor sites (vs. estrogen=2)
- Which activation factor is associated with the ligand binding domain?
AF2
Which of the following exerts the greatest stimulatory effect on the release of GnRH? A) B-endorphin B) Dopamine C) GABA D) Leptin E) Ultradian rhythm
E) Ultradian rhythm
A-C) Inhibitory
D) Permissive
GnRH is released in pulses every 90-120 min. What hormones are preferentially being secreted? A) Androstenedione B) Estradiol C) Luteinizing hormone D) Progesterone
B) Estradiol
FSH–>Estradiol!
Which of the following hormones binds to a ligand binding domain that is very large and associated with activation factor 2 and a DNA binding domain? A) Estradiol B) Follicle Stimulating Hormone C) GnRH D) Luteinizing hormone E) Leptin
A) Estradiol
What are the two gonadotrope independent stages of ovarian follicle development?
Primordial and Pre-antral
Transitioning a follicle from the dormant to the growth phase requires interaction b/t the ovum and granulosa cells.
What is secreted from the ovum that leads to pre-antral–>antral stage?
Step 1:
-Ovum secretes bone morphogenic protein (BMP-15) and growth differentiation factor (GDF) that cause granulosa cells to become cuboidal
Step 2:
-The granulosa cells secrete c-kit (kit ligand…receptor on ovum), which removes the ovum from inhibition that prevents its growth.
Which stage marks the beginning of gonadotrope dependent follicle maturation?
Antral stage (growth)
About 85 days prior to ovulation, hundreds of follicles enter the selection growth phase. What will these follicles secrete?
AMH (anti-Mullerian Hormone)
During the follicluar/proliferative phase, GnRH release is stimulated by time and inhibited by estradiol (neg feedback).
However, the GnRH neurons do NOT express ER.
How does estrogen inhibit GnRH? What are the NT involved?
Incr estrogen»
Decr Kisspeptin/NKB/dynorphin»
Decr GnRH release»
Decr FSH/LH
Polysynaptic pathway: The ER are found on a diff. neuronal pop. in the arcuate nucleus w/ their own NTs. The GnRH neurons in the hypothalamus express receptors for these NT. The NT are:
- **Kisspeptin
- Neurokinin B
- Dynorphin
TQ
T/F
The release of Kiss1/NKB/dynorphin onto the GnRH releasing neurons of the hypothalamus INCREASES GnRH release.
True!
TQ
How does estrogen decrease the release of Kiss1/NKB/dynorphin?
Estrogen response element (nuclear R)
In the follicular phase of the ovary, the high estrogen concentration promotes development of the follicles from the previous cycle that have been chosen in the selection growth phase (AMH).
The ovum that will be ovulated will additionally secrete what factors? why?
- Estrogen–>Incr FSH receptors–>Incr FSH sensitivity….allows the ovum to continue to develop even when the FSH levels fall b/t the two cycles
- Inhibin A and B are also released
During the proliferative phase of the uterus, estradiol from the ovary promotes endometrial growth (1-2 mm to 6-10 mm) by increasing growth factors. What does this lead to?
- Elongated glands (dont secrete)
- Spinal artery extension through increasing thickness
What changes does the myometrium undergo during the proliferative phase?
- Incr expression of oxytocin receptors
- Incr expression of contractile proteins
- Incr excitability of the smooth muscle
(ready to respond to ovulation)
Negative feedback between estrogen and FSH occurs pre-ovulation and during the luteal/secretory phase. Positive feedback between estrogen and LH is required for ovulation. How does this occur?
- A second set of KISS1/NKB neurons are located near the AVPV anteroventral periventricular nucleus (3rd ventricle).
- These neurons express ER but are NOT mediated through the estrogen response element
- Instead, cell membrane R–>phosphorylation of proteins–>incr in GnRH and LH.
Activation of what receptor type leads to apoptosis of thecal cells and eventual ovulation? A) ER-alpha B) ER-Beta C) PR-A D) PR-B E) PR-C
C) PR-A
Ovulation requires the expression of progesterone receptors (PR-A)»
Cytokines and proteases»
Apoptosis of thecal cells»
Follicle rupture and release of ovum
Secretion of what chemical identifies an ovum as having entered the selection growth phase? A) Bone-Morphogenic protein (BMP) B) Anti-Mullerian Hormone (AMH) C) C-kit D) Growth Differentiation Factor (GDF) E) Inhibin A
B) Anti-Mullerian Hormone (AMH)
A, C, D) Before growth phase (pre-antral–>antral…gonadotropin dep)
E) “Ovulated” ovum
A neuron that releases Kisspeptin, NKB, and dynorphin is found to be inhibited when estrogen binds to its receptors. Where is this neuron located? A) AVPV B) Arcuate Nucleus C) Paraventricular nucleus D) Supraoptic nucleus
B) Arcuate Nucleus
- After ovulation, in the luteal and secretory phase, LH stimulates the granulosa and thecal cells to differentiate into granulosa and thecal lutein cells.
- The decr in FSH and incr in LH receptor activity–>expression of different steroid synthetic enzymes, including progesterone.
What are some of the actions of progesterone?
Promotes the secretory function of the endometrium:
- -Glands accumulate glycogen and secrete glycoproteins, proteins, and transudate of plasma–>lumen
- Spiral arteries coil/corkscrew
- Incr capillary permeability (transudate)
- Pre-decidualization occurs–>incr PG (getting ready for implantation)
Decreases excitability/contractility of the myometrium (decr estogen and oxytocin R) w/ continued SM growth (hyperpolarized…no contraction)
About 9 days post-ovulation, the corpus luteum will undergo apoptosis and progesterone levels fall–>shedding of endometrium.
However, if a pregnancy occurs, what prevents the apoptosis?
Human chorionic gonadotropin (hCG)
When apoptosis/regression og the corpus luteum occurs, the endometrium secretes PGF (2alpha) and PGE2.
What do the PG’s do?
(note: The decr in progesterone also triggers secretion of matrix proteases adding to the regression)
Cause spinal arteries to constrict blood flow»
Ischemic endometrium»
Shedding
What is blood loss in menses limited by?
- Blood clots
- Estrogen-induced healing of basalis layer by epithelial cell replacement
GnRH pulses are measured in a women and found to be occurring every 3-5 hours. What else is happening at this time?
A) Uterine glands are elongating
B) Incr oxytocin R expression in myometrium
C) Incr LH secretion
D) Neurons in AVPV secreting Kisspeptin
E) Apoptosis of follicular thecal cells
C) Incr LH secretion
A) follicular/prlife
B) estrogen
D LH surge ovulation
E) Ovulation
Reproductive hormones remain low until age 6. What happens?
GnRH pulses at NIGHT
- Clock, BMAL1, period gene dependent
- DONT lead to significant FSH and LH release (no daytime pulses)
TQ
What causes the GnRH pulses at night at about age 6?
- Catecholamines and EAA (via NMDA) receptors acting on GnRH neurons
- PGE2 (glial cells, triggered by TGFa)
What is important step in the production of puberty and why?
hint: puberty=GnRH–>ultradian pattern
AVPV KISS1/NKB neuron development–>
Positive feedback–>
LH surge
T/F:
If given kisspeptin, onset of puberty is accelerated.
If antagonize its receptor (KISS1R), puberty delayed.
True
Leptin’s role in puberty is permissive:
Which cells involved in GnRH secretion have the leptin receptor?
Note: giving leptin does NOT advance puberty and puberty occurs slowly in leptin deficient individuals.
- KISS1/NKB cells of both the arcuate and AVPV DO….leptin helps them come to threshold
- GnRH releasing cells of arcuate nucleus do NOT express the leptin receptor
- Cessation of menstraul cycles in women at avg age 52 yo
- High gonadotropic hormones, low estrogens, and progesterones
- Exhuastion of the supply of follicles for development
- Failure of follicles to secrete estradiol–>no negative feedback–>FSH LH incr
- Degeneration of KISS1/NKB neurons in AVPV
Menopause
5-year old girl shows GnRH pulses at night. Which NT are producing these pulses?
A) Kisspeptin and dynorphin from AVPVn neurons
B) Kisspeptin from arcuate nucleus
C) Catecholamines and EAA from arcuate neurons
D) PGE2 from AVPV neurons
C) Catecholamines and EAA from arcuate neurons
D) PGE2 from glial cells!
During the uterine cycle, glands secrete glycoprotein and protein rich exudate to provide nourishment before implantation.
What is pre-decidualization?
Changes in the endometrium that will render it “hostile” to implantation
Therefore, Blastocyt has limited window to implant (8-10 days after ovulation)
TQ
- In direct contact with maternal circulation
- Contains machinery for formation of pregnancy hormones such as hCG, hPL, and CRH
Syncytiotrophoblast
What hormone?
- First measurable product of placenta
- Has identical alpha subunit as LH, FSH, and TSH
- **β subunit is more specific (67% homology to LH)…acts like LH to maintain corpus luteum
Human Chorionic Gonadotropin (hCG)
TQ
- What stimulates the release of hCG?
- What are some functions of hCG?
- Stimulus: placental GnRH
- Maintains corpus luteum»>
- Promotes progesterone secretion by corpus luteum
- Fetal testicular testosterone secr.
- Maternal thyroid stimulation
- Peaks @ 10 wks then decr.
What hormone?
- Human somatomammotropin
- Part of growth hormone family
- Detectable levels @ 4-5 weeks gestation
- Secretion approaches 1g/day!!
- Control of secretion: constitutive?
Human Placental Lactogen (hPL)
What are some functions of hPL?
Hint: member of GH family
- Contributes to altered glucose metabolism in woman (diabetogenic)
- Mobilizes free fatty acids
- Directly stimulates release of insulin
- Contributes to insulin resistance associated with pregnancy
- Maybe angiogenic to fetal vasculature
