Menstrual Cycle and Ovulation (Creamer)

Question 1

Schematic of the menstrual cycle hormonal changes:

Answer 1

Question 2

Describe ovulation in terms of stages of meiosis:

Answer 2

• meiotic arrest (prophase I): elevated levels of cAMP; large antral follicles gain meiotic competence (stay is arrest until LH surge, can stay in this stage ~50 years)
• meiosis I finishes before ovulation: polar body 1 extruded
• meiotic arrest (metaphase II): elevated levels MAPK proteins
• resumption of meiosis II only at fertilization: rapid degradation of MAPK, polar body 2 extruded

Question 3

What are the 3 phases of the ovarian cycle?

Answer 3

• follicular phase
• ovulatory phase
• luteal phase

Question 4

• functional until of the ovary
• performs gametogenic and endocrine functions
• pre-menopausal cycling ovary contains follicular structures at many different stages

Answer 4

ovarian follicle

Question 5

Describe the follicular phase of the ovarian cycle:

Answer 5

• the follicle selected for that particular month begins to grow
• follicular phase starts with the first day of your period and ends with ovulation
• each follicle houses a primary oocyte arrested in prophase I
• most developed Graafian follicle releases its oocyte during ovulation
• as that primary oocyte is released, it finishes its first meiotic division, becoming a secondary oocyte (arrested in metaphase II)

Question 6

What are the steps of the follicular phase?

Answer 6

1) resting primordial follicle
2) growing preantral (primary and secondary) follicle
3) growing antral (tertiary) follicle
4) dominant (preovulatory, graafian) follicle
5) dominant follicle within periovulatory period
6) corpus luteum (of menstruation or of pregnancy)
7) atretic follicles

Question 7

• primary oocyte arrested in prophase I (can remain for 50 years)
• surrounded by a single layer of pregranulosa cells
• release paracrine factors, no seroid hormones
• represents the ovarian reserve, of which most will undergo atresia (400-500 develop and ovulate)

Answer 7

primordial follicle

Question 8

• central primary oocyte
• single layer of granulosa cells take on cuboidal shape
• increase in size of follicle due to growth of primary oocyte
• early production of secreted glycoproteins: ZP1, ZP2, ZP3, ZP4

Answer 8

primary follicle

Question 9

• primary oocyte surrounded by 3-6 layers of cuboidal granulosa cells
• secretion of paracrine factors to induce local stromal cells to differentiate into thecal cells: inner glandular highly vascular theca interna, fibrous capsule-like theca externa

Answer 9

secondary follicle

Question 10

How does progression into secondary follicle occur?

Answer 10

• involves increased vascularization
• migration from outer cortex to inner cortex, closer to ovarian vasculature
• follicles release angiogenic factors that induce development of 1-2 arterioles: generates vascular wreath around follicle
• zona pellucida development occurs: provides binding sites for sperm during fertilization

Question 11

What type of hormonal signaling occurs during growth of preantral follicles?

Answer 11

• minimal endocrine function
• granulosa cells express FSH receptors, primarily dependent on paracrine factors from oocyte for growth
• granulosa cells do not produce ovarian hormones at this point
• thecal cells are analagous to testicular Leydig cells: express LH receptors, major product is androstenedione (although at this point production is minimal/absent)

Question 12

Describe the antral phase of the follicular phase of the ovarian cycle of the menstrual cycle:

:)

Answer 12

• appearance of the antrum marks beginning of antral phase
• oocyte becomes suspended in fluid surrounded by a dense mass of granulosa cells (cumulus oophorus)
• two populations of granulosa cells develop: mural granulosa (stratum granulosum) and cumulus cells (cumulus oophorus/corona radiate)
• follicle growth becomes responsive to androgens during this phase
• oocytes grow rapidly during this stage, which slows in larger follicles
• oocyte becomes competent to complete meiosis I at ovulation: oocyte synthesizes sufficient amnts of cell cycle components (e.g. cyclin-dependent kinase 1, cyclin B); larger follicles gain meiotic competence but still maintain meiotic arrest until midcycle LH surge; meiotic arrest is maintained by elevated cAMP levels in mature oocyte)
• increase in follicular size depends on: increase in antral size, volume of follicular fluid, proliferation of granulosa cells

Question 13

What are the 2 distinct granulosa cell populations that develop during the antral phase of follicular development?

Answer 13

(100-fold increase in granulosa cells occurs)

• mural granulosa (stratum granulosum): outer wall of follicle, become highly steroidogenic
• cumulus cells (cumulus oophorus/corona radiata): maintain gap and adhesion junctions w/ oocyte; released during ovulation w/ oocyte

Question 14

When does follicle growth become responsive to gonadotropins?

Answer 14

• during the antral follicle growth phase
• theca interna - LH: synthesize androgens from acetate and cholesterol; androstenedione is major steroid product; limited estrogen synthesis
• granulosa - FSH: convert androgens from thecal cells (granulosa-mediated aromatization of androgens to estrogens, stimulated by FSH); induces expression of LH receptors late in follicular phase

Question 15

How does FSH play a role in selection for follicle for ovulation?

Answer 15

• several large antral follicles are recruited to begin development each monthly cycle
• selection of 1 dominant follicle occurs early in follicular phase
• mural granulosa produce low levels of estrogen and inhibin B
• FSH levels decline: largest follicle w/ most FSH receptors (highest sensitivity) becomes dominant follicle; other follicles undergo atresia (apoptosis of oocytes and granulosa cells)
• midcyle, dominant follicle becomes a large preovulatory follicle (Graffian follicle)

Question 16

Describe the periovulatory period:

Answer 16

• time from onset of LH surge to ovulation: 32-36 hours
• structural changes occur to prepare for ovulation
• changes in steroidogenic function of theca and mural granulosa occur: prepares for luteinization, formation of corpus luteum, increased production of progesterone

Question 17

What changes occur with the LH surge in terms of granulosa cells?

Answer 17

• LH surge induces differentiation (luteinization) of granulosa to granulosa lutein cells
• thecal and mural granulosa cells express LH receptors at surge which induces a shift in steroidogenic activity
• transient inhibition of aromatase expression: rapid decline reduces positive feedback on LH secretion
• increased vascularization of granulosa occurs: increases cholesterol availability for progesterone production

Question 18

What structural changes occur w/ LH surge?

Answer 18

• release of cytokines and hydrolytic enzymes from theca and granulosa: breakdown of follicle wall, tunica albuginea, surface epithelium
• cumulus-oocyte complex detaches (free floating in antrum)
• basal lamina of mural granulosa degraded: angiogenic factors released, increased blood supply to follicle/corpus luteum

- LH surge induces oocyte to progress to metaphase II

Question 19

What occurs during the luteal phase of ovarian cycle?

Answer 19

• LH surge causes granulosa differentiation and structural changes (increases vascularization), and induces oocyte to progess to metaphase II
• antral cavity fills w/ blood/cell debris: corpus hemorrhagicum, removed by macrophages
• granulosa lutein cells collapse into antral cavity: filled w/ cholesterol esters; theca, blood vessels, white blood cells fill remainder of cavity; often yellow in color due to carotenoid pigment (lutein)

Question 20

Describe the corpus luteum of menstruation:

Answer 20

• remains ~14 days
• becomes corpus albicans: scar-like body, primarily collagen
• if rescued by hCG from conceptus, will remain viable for duration of pregnancy (similar in structure to LH)

Question 21

Describe the corpus luteum of pregnancy:

Answer 21

• CL produces increasing progesterone: transforms uterine lining into adhesive and supportive structure, important for implantation and early pregnancy
• transient decrease in estrogen following LH surge, rebounds and peaks midluteal phase
• progesterone and estrogen reduce LH to basal levels: hCG compensates for this decline
• lutein cells secrete inhibin A, suppresses FSH

Question 22

• demise of an ovarian follicle
• predominant process in the ovary
• can occur at any time during development
• during this process, granulosa cells and oocytes undergo apoptosis
• thecal cells persist and repopulate cellular stroma of the ovary: retain LH receptors and ability to produce androgens, collectively are referred to as interstitial gland of the ovary

Answer 22

follicular atresia

Question 23

Describe the hypothalamic-pituitary-ovarian axis:

Answer 23

• hypothalamic neurons synthesize/store/release GnRH
• GnRH binds to receptors on gonadotropins, resulting in synthesis/release of FSH/LH
• FSH and LH stimulate ovaries to synthesize/secrete estrogens and progestins
• ovaries (granulosa cells) also produce inhibin and activin peptides
• ovarian steroids and peptides exert both negative and positive feedback on both hypothalamus and anterior pituitary

Question 24

How does pulsatile release of GnRH affect LH secretion?

Answer 24

• early in follicular phase, gonadotrophs are not very GnRH sensitive, each burst of GnRH only elicits a small rise in LH
• later in the follicular phase, gonadotrophs in anterior pituitary become much more sensitive to GnRH in portal blood, each burst of GnRH triggers a much larger release of LH

Question 25

How do FSH and LH affect ovarian cells?

Answer 25

- FSH and LH stimulate ovarian cells to secrete estrogens and progestins - **before ovulation**: LH and FSH act on cells of developing follicles; theca cells have LH receptors, whereas granulosa cells have both LH and FSH receptors; both LH and FSH are required for estrogen production b/c neither theca cells nor granulosa cells can carry out all required steps - **after ovulation**: LH acts on cells of corpus luteum

Question 26

What is the role of inhibins in the ovarian cycle?

Answer 26

- produced by granulosa cells of follicle (ovaries) - FSH specifically stimulates granulosa cells to produce inhibins - just before ovulation, after the granulosa cells acquire LH receptors, LH stimulates production of inhibin by granulosa cells - **inhibins inhibit FSH production by gonadotrophs of the anterior pituitary**

Question 27

What is the role of activins in the ovarian cycle?

Answer 27

- produced by granulosa cells of the follicle (ovaries) - **stimulate FSH release from pituitary cells which is independent of GnRH action** - intraovarian action of stimulating synthesis of estrogens

Question 28

Describe the negative feedback on the hypothalamic-pituitary axis by ovarian steroids:

Answer 28

- throughout most of menstrual cycle, estrogens and progestins feed back negatively on hypothalamus and pituitary - net effect is to reduce LH and FSH release - estrogens exert negative feedback at both low and high conc, whereas progestins are effective only at high conc

Question 29

Describe the positive feedback on the hypothalamic-pituitary axis by ovarian steroids:

Answer 29

- ovarian steroids exert positive feedback at the end of the follicular phase - levels of estradiol rise gradually during the 1st half of the follicular phase of the ovarian cycle and then steeply during the 2nd half - after estradiol levels reach a certain threshold, for a minimum of 2 days, HP axis reverses its sensitivity to estrogens, and now exerts a positive feedback: **switch to positive feedback promotes LH surge** - rising levels of progesterone during late follicular phase also produce positive feedback response and thus facilitate the LH surge

Question 30

Describe the cyclic hormonal changes during the menstrual cycle:

Answer 30

- positive feedback of estrogens, progestins, and activins on HP axis is involved in induction of **LH surge** - as luteal phase of menstrual cycle begins, circulating levels of LH and FSH rapidly decrease: this fall-off in gonadotropin levels reflects negative feedback by estradiol, progesterone, and inhibin; as gonadotropin levels fall, so do levels of ovarian steroids - during luteal phase, the rise in conc of estradiol, progesterone, and inhibin causes continued decrease of gonadotropin levels midway through luteal phase: during late luteal phase, gradual demise of corpus luteum leads to decreases in levels of progesterone, estradiol, and inhibin - after onset of menstruation, HP axis returns to a follicular-phase pattern of LH secretion (i.e. gradual increase in frequency of GnRH pulses)

Question 31

What is the major hormonal product during the follicular phase?

Answer 31

- **estradiol** - follicle synthesizes estrogens during follicular phase, whereas in luteal phase the corpus luteum does the synthesis - estradiol synthesis requires contribution of 2 distinct cell types: theca and granulosa cells within the **follicle** and theca-lutein and granulosa-lutein cells within the c**orpus luteum**

Question 32

What is the major hormonal product during the luteal phase?

Answer 32

- major products of **corpus luteum are progestins** - estradiol synthesis is still substantial

Question 33

How does body temp change during menstruation? What regulates this?

Answer 33

- **hormones regulate basal body temp during menstrual cycle** - higher levels of estrogen present during pre-ovulatory (follicular) phase of menstrual cycle lower BBT - higher levels of progesterone released by corpus luteum after ovulation raise BBT: rise in temp can most commonly be seen day after ovulation - if pregnancy does not occur, the disintegration of corpus luteum causes a drop in BBT that roughly coincides w/ onset of next menstruation

Question 34

Describe the menstrual phase of the endometrial cycle:

Answer 34

- if oocyte is not fertilized and pregnancy does not occur, a sudden diminution in estrogen and progesterone secretion signals demise of corpus luteum - as hormonal support of endometrium is withdrawn, endometrium degenerates, tissue breaks down, and menstrual bleeding occurs (this is defined as day 1 of menstrual cycle)

Question 35

Describe the proliferative phase of the endometrial cycle:

Answer 35

- after menstruation, the endometrium is restored ~5th day of cycle - proliferation of basal stromal cells in zona basalis - proliferation of epithelial cells from other parts of the uterus - stroma gives rise to CT components of endometrium - proliferation/differentiation of endometrium are stimulated by estrogen (secreted by developing follicles) - levels of estrogen rise early in follicular phase and peak just before ovulation: estrogen causes stromal components of endometrium to become highly developed, estrogen also induces synthesis of progestin receptors in endometrial tissue

Question 36

Describe the proliferative phase of the endometrial cycle:

Answer 36

- final phase of the endometrial cycle, corresponds to the luteal phase of the ovarian cycle - middle to late secretory phase: vascularization/glycogen content of the endometrium increases; endometrial glands become engorged w/ secretions; **progesterone** promotes differentiation of stromal cells into **predecidual cells**, which must be prepared to form the **decidua** of pregnancy, or to orchestrate menstruation in the absence of pregnancy

Question 37

- defined as occurring 12 months after the last menstrual period, marks end of menstrual cycles - occurs at 51.4 y/o on average - due to reduction in estrogen, low levels of inhibin: **no negative feedback of LH and FSH, therefore high levels of LH and FSH** - can occur naturally, prematurely (premature ovarian failure), due to surgery, or as a result of chemotherapy - months leading up: irregular periods, vaginal dryness, hot flashes, night sweats, mood changes, weight gain, slow metabolism, thinning hair, dry skin, loss of breast fullness - tx: estrogen therapy, vaginal estrogen, low-dose antidepressants, Gabapentin (hot flashes)

Answer 37

menopause