Lecture 10: Histology and Physiology of the Menstrual Cycle Flashcards
1
Q
Puberty in girls involves what 3 things?
A
1) Thelarche: breast development
2) Adrenarche: increase in adrenal androgen secretion
3) Menarche: beginning of menstrual cycles
2
Q
Hypothalamus neurons synthesize, store and release GnRH in what type of manner?
A
Pulsatile manner
3
Q
What are the main hormonal products of Ovarian Theca Cells vs. Granulosa Cells?
A
Ovarian Theca Cell
- Androgens
- Progestins
Ovarian Granulosa Cell
- Estrogen
- Inhibin
4
Q
Females are born w/ 1-2 million ova arrested in; what nourishes them and keeps them arrested?
A
Prophase I
- Known as primordial follicles
Granulosa Cells
- Nourish primordial follicles
- Produce oocyte maturation inhibiting factor
5
Q
Which phase of the ovarian cycle coincides with proliferative phase of endometrial cycle and which coincides with the secretory phase of the endometrial cycle?
A
Follicular phase = proliferative phase
Luteal phase = secretory phase
6
Q
What are the 3 phases of the Endometrial cycle?
A
1) Menses (menstrual phase)
2) Proliferative phase
3) Secretory phase
7
Q
Which hormone stimulates a follicle to complete its development; begins with onset of and ends on day of?
A
- FSH
- Begins with onset of menses
- Ends on day of LH surge (14 days)
8
Q
What causes the surge of LH leading to ovulation?
A
Granulosa cells of follicles increase production of estradiol and rapid rise in estradiol secretion eventually triggers a surge in LH
9
Q
What do the follicles transform into during lueal phase and what do luteal cells produce?
A
- Transforms into a corpus luteum
- Produce progesterone and estrogen, which stimulate further endometrial growth and development
10
Q
What is occuring with negative feedback and hormone secretion 2 days prior to menstration?
A
- Release of neg. feedback on hypothalamus and pituitary
- Increases production of FSH
11
Q
What is occuring on day 1 of menstruation via FSH and the follicles?
A
- FSH recruits several follicles
- Follicle produce low concentrations of estrogen and inhibin B
- Neg. feedback causes a decrease in FSH
12
Q
Low levels of estrogen and inhibin B production during the follicular phase of ovulation lead to what?
A
- Decreased FSH, which decreases progesterone and estrogen prod.
- Increased frequency of GnRH pulsations, which lead to increased LH and an increases LH/FSH ratio
13
Q
What is the sensitivity of the gonadotrophs to GnRH early in the follicular phase vs. later in the follicular phase?
A
- Early they are not very GnRH sensitive; each pulsatile burst only elicits a small rise in LH
- Later they become much more sensitive to GnRH in the portal blood and a much larger release of LH is triggered
14
Q
What enhances the sensitivity of the gonadotrophs to GnRH late in the follicular phase?
A
High levels of estradiol produced by the ovarian granulosa cells
15
Q
Which receptors are on Theca cells vs. Granulosa cells and what is required for estrogen production?
A
- Theca cells have LH receptors
- Granulosa cells have both LH and FSH receptors
- Both LH and FSH are required for estrogen production because neither theca cells nor granulosa cells can carry out all the required steps
16
Q
Which cells produce inhibins, when is it produced, and what is their action?
A
- Produced by Granulosa Cells in response to FSH
- Just before ovulation, after granulosa cells acquire LH receptors, LH also stimulates the production of inhibin
- Inhibits FSH production by gonadotrophs
17
Q
Where are activins produced and what do they do?
A
- Produced by the granulosa cells
- Stimulate FSH release
18
Q
Throughout most of the menstrual cycle, estrogens and progestins have what effect on the HP-axis; what is the net effect?
A
- Negative feedback on the hypothalamus and anterior pituitary
- Net effect is to reduce LH and FSH release
19
Q
Does the concentration of estrogens and progestins matter for them to exert neg. feedback?
A
- Estrogens extert neg. feedback at both low and high concentrations
- Progestins are effective only at high concentrations
20
Q
When is there a switch to positive feedback during the follicular phase, what hormones are involved, and what does this lead to?
A
- Estrogen levels rise gradually during the 1st half of the follicular phase and then rise steeply during the 2nd half
- Progesterone levels rise during late follicular phase
- HP axis reverses its sensitivity to estrogens and progesterone after levels reach a certain threshold, for a minimum of 2 days
- Switch to positive feedback promotes the LH surge
21
Q
What does the fall-off of gonadotropin (LH and FSH) levels at the beginning of the luteal phase reflect?
A
Negative feedback by estradiol, progesterone, and inhibin.
22
Q
After the onset of menstruation, what happens to the HP axis?
A
Returns to a follicular-phase pattern of LH secretion (i.e., gradual increase in the frequency of GnRH pulses)
23
Q
Where can estrogens be derived from?
A
- Ovary
- Adrenal gland
- Peripheral conversion in adipose tissue
24
Q
What is the primary circulating estrogen in non pregnant women?
A
Estradiol
25
What enzymes do the granulosa cells of the ovary have to make estrogen and how?
- Aromatase converts **androstenedione to estrone**
- Aromatase converts **testosterone to estradiol-17β**
- 17β-HSD converts **androstenedione to testosterone**
- 17β-HSD converts **estrone to estradiol-17β**
26
What is the weaker estrogen produced during pregnancy and where?
Estradiol and Estrone converted to **Estriol** in the **liver**
27
Where is aromatase activity absent and where is 17α-hydroxylase and 17,20-desmolase activity absent during the follicular phase?
- Aromatase is absent in the Theca cells
- 17α-hydroxylase and 17,20-desmolase absent in Granulosa cells
28
During the follicular phase what is the major product; how is it produced?
- Estrogen
- Produced in coordination between Theca cells and Granulosa Cells
29
During the luteal phase what is the major hormone product, what else is produced and by what cells?
- Progesterone is the major product. although estradiol synthesis is substantial
- Produced in coordination between Theca lutein cells and Granulosa lutein cells
30
Histologically the uterus contains 3 layers what are they and what are they composed of?
**1) Endometrium (mucosa)**
Superficial functional layer
- Simple columnar epithelial lining
- Simple tubular endometrial glands
Basal layer
- Source of regeneration
**2) Myometrium**
- Inner longitudinal
- Middle circular layer called stratum vasculare
- Outer longitduinal
**3) Adventitia or serosa (perimetrium)**
31
Which layer of the uterus is lost during menstruation and which part is the source of regeneration?
- Superficial functional layer of the endometrium (mucosa) is **lost**
- Basal layer of the endometrium (mucosa) will **regenerate**
32
Label A-E of the Uterus
A) Stratum Functionalis
B) Endometrium
C) Stratum Basalis
D) Myometrium
E) Serosa
33
What is the main artery and its branches that supply the endometrium of the uterus?
- Arcuate artery
- **Straight segment:** supplies the basal layer
- **Coiled segment:** supplies the functional layer, stretches w/ endometrial growth
34
Before menstruation contraction of the arcuate artery occurs where; what does this cause?
- At the **straight-coiled junction**
- Reduces blood flow and causes **necrosis/destruction** of the **functional layer**
35
What 2 time perioids is body temperature (BBT) decreased during the menstrual cycle and what causes this?
- Higher levels of **estrogen** during the **pre-ovulatory** (**follicular**) **phase** of the menstrual cycle lower BBT
- If pregnancy does **no**t occur, the **disintergration** of the **corpus luteum** causes a drop in BBT that roughly coincides w/ the onset of the next menstruation
36
When do we see a raise in body temperature durin the menstrual cycle and what causes this?
Higher levels of **progesterone** released by the **corpus luteum** after ovulation raise BBT
37
What occurs during the menstrual cycle if the oocyte is not fertilized and pregnancy does not occur in the previous cycle; what is this moment defined as?
- A sudden decrease in estrogen and progesterone secretion signals the demise of the corpus luteum
- As hormonal support of the endometrium is withdrawn, the **degenerates**, the tissue **breaks down**, resulting in **menstrual bleeding**
- This moment is defined as **day 1** of the menstrual cycle
38
What are the 4 events occuring at day 1 of the menstrual cycle involving the spiral arteries, glands, neutrophils and shedding of material?
1) Spiral arteries begin contracting at junction w/ straight arteries
- Necrosis of endothelial cells --\> decrease O2 to functional layer
2) Endometrial glands in functional layers become necrotic and detach
3) Neutrophils and lymphocytes infiltrate stroma
4) Shed material includes fragment of stroma, blood clots, and pieces of glands
39
What phase of the endometrial cycle is this?
Proliferative phase
- Functional layer is relatively thin
- Stroma is more cellular
- Glands relatively **straight**, narrow, & empty
40
What phase of the endometrial cycle is this?
Menstrual phase
41
After menstruation the endometrium is restored by the 5th day during the proliferative phase of the cycle, how does estrogen contribute to this?
- Levels of estrogen rise early in the follicular phase
- Estrogen causes the stromal components of the endometrium to become highly developed
- Estrogen induces the synthesis of progestin receptors in the endometrial tissue
42
How does progesteone oppose the effects of estrogen on the epithelial cells of the endometrium?
- Inhibits epithelial cells proliferation but promotes proliferaton of the endometrial stroma
- Stimulates 17β-HSD and sulfotransferase (convert estradiol to weaker compounds)
43
Explain what happens histologically during the last 9-10 days of the proliferative phase to the functional layer, spiral arteries, and endometrial glands?
1. Functional layer begins to **thicken**, epithelium **regenerates** (due to increased circulating **estrogen** from ovarian follicle)
2. Spiral arteries are **deep** in the endometrium and are **short**
3. Endometrial glands are **short, straight, and empty --\>** start growing longer
44
What phase of the endometrial cycle is shown here and how do you know?
- Proliferative phase
- Straight and short glands
- Surface epithelium layer is beginning to smooth out
45
What is the final phase of the uterine cycle (endometrial cycle) and what phase of ovarian cycle does it correspond with?
Secretory phase is final phase of uterine cycle (endometrial cycle) and corresponds to the luteal phase of the ovarian cycle
46
What is the early secretory phase of the uterine cycle characterized by; stimulated by?
Early phase:
- Development of a network of interdigitating tubes within the nucleolus of the endometrial epithelial cells (nucleolar channel system); **stimulated by progesterone**
47
What is the middle/late phase of the secretory phase of the uterine cycle characterized by; what is the specific role of progesterone here in regards to preparation for pregnancy or menstruation?
- **Increase** in the **vascularizaion, glycogen content and thickness** of the endometrium
- Endometrial **glands** become **engorged** with **secretions**
- **Progesterone** promotes the differentiation of the stromal cells into **predecidual cells,** which must be prepared to form the **decidua** of pregnancy, or to ochestrate menstruation in the absence of pregnancy
48
Histologically what is seen during the secretory/luteal phase in regards to the functional layer, spiral arteries, and endometrial glands?
1. Functional layer becomes very thick (increased cells, edema, and ground substance)
2. Spiral arteries become **long**, grow superficially, and form **small lacunae of blood**
3. Endometrial glands become **tortuos** and **hypertrophied** w/ glycogen-rich secretory products
49
What phase is this and how do you know?
- Secretory phase
- Continous surface epithelium
- Glands have zigzag, saw-tooth shape
50
What phase is this and how do you know?
- Secretory phase
- Surface epithelium is continous
- Glands are zigzag, saw-tooth shape
51
What phase is this and how do you know?
- Proliferative phase
- Glands are relatively staight, narrow, and empty
52
What phase is this and how do you know?
- Secretory phase
- Tubular glands have lumens w/ secretory product
- Glands coil and form zigzag, saw-tooth shape
53
Histologically what are the 3 layers of the Uterine Tubes?
**1. Mucosa**
- Simple columnar epithelium
- Ciliated cells
- Nonciliated secretory cells
**2. Muscle (smooth)**
- Inner circular layer
- Outer longitudinal layer
**3. Serosa**
54
Histologically what are the 2 parts of the cervix and what is each composed of; which secretes mucus and where can cysts form?
**1. Endocervix:**
- Simple columnar epithelium
- Mucous secreting
- Nabothian cysts
**2. Endocervix:**
- Stratified squamous epithelium
- Continous w/ the vaginal epithelium
55
Label A and B on this picture of the Cervix
A) Endocervix: simple columnar
B) Ectocervix: startified squamous
56
What is the squamous-columnar junction of the cervix referred to and why is it clinically relevant?
- Transformation zone
- Where squamous cells become metaplastic and are going to replace the columnar cells of the endocervix.
- Cells undergoing metaplasia are much more sensitive to **HPV** and cells in this zone are at the highest risk of infection by **HPV**
- **Adenocarcinomas** may affect the columnar cells of the **endocervix**
57
Label A-C of the Cervix
A) Simple columnar epithelium
B) Squamous-columnar junction
C) Stratified squamous epithelium
58
The vagina is what kind of tube and is histologically composed of what 3 layers?
- Fibromuscular tube
1) **Mucosal layer**: stratified squamous epithelium
- Lamina propria - **no glands**
- Undergoes cyclic changes during menstrual cycle
2) **Muscularis layer**
- Circular and longitudinal smooth muscle
3) **Adventitial layer**
59
Which histological layer of the vagina is usually infiltrated by neutrophils and lymphocytes and undergoes cyclic changes during menstrual cycle?
- Mucosal layer undergoes changes during menstrual cycle
- Lamina propria w/ **no glands** is infiltrated by neutrophils and lymphocytes
60
Which reporductive strucutre is this?
Vagina
61
Which reproductive structure is this?
Vagina
62
Oral contraceptives feedback to where and cause what?
- Feedback both **directly** at the level of the **hypothalamus** (decrease GnRH) and at the level of the gonadotrophs in the **anterior pituitary**
- Net effect is **suppressed FSH and LH**
- Low FSH levels are insufficient to stimulate normal folliculogenesis; the low LH levels prevent an LH surge and therefore inhibit ovulation
63
What is the progestin effetc of oral contraceptive pills?
- Causes the cervical mucus to **thicken** and become **sticky/insufficient**
- Progestins **impair** the **motilit**y of the uterus and oviducts, **decreasing transport of both ova and sperm** to normal site of fertilization
64
What is Endometriosis; most commonly affected tissues?
- Painful disorder in which endometrial glands that normally grow inside the endometrial cavity grow outside of it
- Most commonly involves the ovaries, bowel, or peritoneum lining the pelvis
65
What are the common clinical signs and symptoms presented w/ endometriosis?
- Chronic pelvic pain linked to menses
- Dysmenorrhea (painful, sometimes disabling cramps during menstrual period)
- Dyspareunia (painful sex)
- Rectal pain and constipation
- Infertility
66
What is seen hormonally in Polycystic Ovarian Syndrom (PCOS)?
- Continous secretion of LH --\> Ovarian enlargement
- Increased LH --\> **excess androgen** production (**theca cells**)
- **Elevated** levels of **androgens** in **adipose tissue** are converted to **estrone** by aromatase
- **Increased estrone** feedsback to **inhibit FSH** secretion
- **Decreased FSH** inhibits follicular maturation and decreases production of **17β-estradiol**
67
What are common symptoms seen in Polycystic Ovarian Syndrom (PCOS)?
- Menstrual dysfunction (amenorrhea)
- Hyperandrogenism (acne, **hirsuitism**, male pattern hair loss)
- Polycystic ovaries
- Metabolic issues/cardiovascular risks (obesity, **insulin resistance, type II DM**)
- Most common cause of **infertility**
68
What is Turner Syndrome, most common cause of, internal/external genitalia are what sex, what happens to the ovaries and hormone levels?
- Most common cause of congenital (**primary**) hypogonadism
- Due to **loss** of part or all of an **X chromosome**
- Internal and external genitalia: **female**
- Ovarian failure --\> **Increased [serum FSH]**
- Germ cells do not develop, ovaries appear as CT filled streak ("**streak ovaries**")
69
What are the characterisitcs seen in a person w/ Turner Syndrome?
- Short stature
- Shield chest
- Bicuspid aortic valve
- Coarctation of the aorta
- Low set ears
- Short 4th metacarpals
- Lymphatic defects (webbed neck or cystic hygroma, lymphedema)
- Sexual infantilism
- Amenorrhea
70
Menopause is defined as what; caused by?
- **12 consecutive months** without menstruation
- Cycles become irregular, then cease
- Avg. age **51.4 years**
- Can occur **naturally**, due to **premature ovarian failure**, **surger**y, or as a result of **chemotherapy**
71
What are the levels of estrogen, inhibin, LH and FSH like in menopause; what becomes the primary form of estrogen in a post-menopausal woman?
- **Reduction** in **estrogen**, low levels of **inhibin**
- **No negative feedback of LH and FSH**; therefore, **high levels LH and FSH**
- Estrone, synthesized from circulating androgens, becomes primary form of estrogen
72
What is the main goal of treatments for Menopause and what are some of the treatments?
- Relief of signs and symptoms
- **Estrogen therapy**: vaginal, topical, oral
- **Low-dose antidepressants**
**- Gabapentin (for hot flashes)**
- Management of co-morbid conditions
73
What phase is the dominant/graafian follicle arrested in; when does it complete this phase; what is the next phase it will be arrested in and when is this phase completed?
- Arrested in Prophase I until release at ovulation
- Will then be arrested in Metaphase II, until fertilization
- Upon fertilization it will complete Meiosis II
74
Is this an early or late placenta? Label A, B and the circled structure?
- Early placenta (lack of fibrin/oid and cytotrophoblast are still present)
A = Cytotrophoblast
B = Syncytiotrophoblast
Circle = Hofbauer Cell
75
Label A - E and what structure would be found between D and C?
A) Ovarian Stroma
B) Theca Externa
C) Theca Interna
D) Granulosa Cells
E) Follicular Fluid
1) Basement membrane of the follicle
