10: The Menstrual Cycle Physio Flashcards
Describe the basis of the menstrual cycle
Out menstrual cycle describes the changes to our ovarian follicles and endometrium that occur post-pubert in F. It lasts 28 days; from 1 period -> next. It made up of 2 phases:
- Ovarian cylcle
- Endometrial cycle
Ovulation (release of a. mature. egg) occurs at mid-menstrual cycle (day 14).
Pre-ovulatory period (days 1-14)
- Ovarian cycle: follicular phase. (maturion of follicle and oocyte)
- Endometrial cycle: (menstrual phase and proliferative phase)
Post ovulatory. period (days 14-28)
- Ovarian cycle: luteal phase (what occurs with remant of follicle and oocyte)
- Endometrial cycle: secretory phase.
Puberty marks the transition to a cyclic, adult reproductive function.
Girls undergo thelarche, adrenarche and menarche during puberty.
Describe that these words mean.
- Thelarche -> breast develpoment
- Adrenarche -> increase in adrenal androgen secretions
- Menarche -> beginging of period.
How do levels of gonadotropins change through life of a female?
- B4 puberty, GnRH is released steadily at LOW levels.
- At puberty, we begin to see oscillartory pulses of gonadotropin being released in REM sleep.
- After puberty and in reproductive years (after 14), it is released in pulses at day and night, causing small surges of FSH release and large surges of LH release
- Sensoscence: Decreased levels of estrogen cause high levels of FSH/LH (higher FSH) secretion d/t menopause. We will see highest levels of steadily released FSH and LH.
The ovary can be divided into what?
Outer cortex and inner medulla, where neurovascular elements run though.
What makes up the CTX of the ovary?
- Dense cellular stroma surrounded b simply epithelium.
- Ovarian follicles are located in the stroma and contain a primary oocyte.
The process of _________ involves inflammatory events that e_rode the wall of the ovary and follicle._
Ovulation
What is the functional unit of the ovary?
Ovarian follicle
What is the ovarian cycle?
Ovarian cycle has 2 phases:
-
Follicular phase
* Days 1-14, leading up to ovulation on day 14
* Coincides with proliferative phase of endometrium cycle)- maturation of the ovarian follicle, competing to grow the fastest so one can be ovulated.
-
Follicular phase
-
Luteal phase
* The following 14 days after ovulation
* Coincides with secretory phase of endometrial cycle).
-
Luteal phase
What is the endometrial cycle?
3 phases:
- Menses (menstrual phase)
- Proliferative phase
- Secretory phase
LETS START WITH OVARIAN CYCLE
LETS START WITH OVARIAN CYCLE
LETS START WITH OVARIAN CYCLE
LETS START WITH OVARIAN CYCLE
Follicle goes through what stages?
- Resting primordial follicles
- Growing preantral follicles
- Growin antral follicles
- Dominant (preovulatory, graafian) follicle
- Dominant follicle within the periovulatory period
- Corpus luteum (of menstruation or pregnancy)
- Atretic follicles (degenerate before coming mature)
Oocyte maturation produces what?
Follicles mature from primordial -> graafian (preovulatory) follicles to create a
Haploid female gamete that can be fertilized be a sperm, begining in the female ovary.
_________ is the earliest and simplest follicular structure in the ovary.
Describe this cell.
Primordial follicle
1 layer pregranulosa cells
Releases paracrine factors, but not hormones.
4N DNA
First primordial follicle usually appears_____ into intrauterine life;
generation of primordial follicles is done by _____months after birth
6 weeks
5-6. months
__________ restrains the development of too many primordial follicles
AMH
Do all of our primordial follicles (4N DNA) enter follcular growth?
No. Primordial follicles are our primordial reserve, which most will be lost d/t atresia. Only a small subset (400-500) grow).
The rate at which _______________ die/develop determines reproductive lifespan of a woman.
resting primordial cells.
What gamete is located inside primordial follicles?
- Primary oocytes arrested in the 1st meiotic prophase and can remain for 50 years.
Primordial follicles develop into what?
Growing preantral follicles
- Primary follicle (4N DNA): primary oocyte surrounded by single layer of granulosa cells that begin to secrete fluid and zona pellucida begins to develop.
-
Secondary follicle (4N DNA): primary oocyte surrounded by 3-6 layers of granulosa cells. Once this happens, paracrine factors are secreted and cause stromal cells -> thecal cells.
* Zona pellucida develops even more to provide binding site for sperm.
When can we refer to a secondary follicle as a mature preantral follicle?
Once thecal layer forms.
The progression to secondary follicles involves what?
-
Increased vascularization;
- follicle moves from outer CTX -> inner CTX, closer to vascularizatture of ovarian medulla.
- They will then release angiogenic factors that make arterioles, which. make a. sheath. around the follicle.
What happens to the gamete in the. growing preantral follicle
- Oocytes are arrested. is meisosis. I. prophase.
- Oocyte begsin to grow and make/secrete proteins, such as ZP1, ZP2, and ZP3 that will make the. zona pellucida, which makes a. binding site for sperm.
- Granulosa cells and oocytes have extensions through. the zona. pellucida and maintain. junctional contacts ,allowing for communication. and nutrition
*
What is the endocrine functions of the growing preantral follicles?
They have LITTLE endocrine function.
Granulosa cells. will have FSH receptors, but depemnd on paracrine factors from oocyte to grow. They will not make hormones at this point.
What are thecal cells analogous to in males?
What do they do during the growing pre-antral follicles?
- Leydig cells.
- Thecal cells have LH receptors and make androstenedione.
- In growing preantral follicles, thecal cells make LITTLE/none androstenedione.
The development of an antrum depens on what?
antrum- > fluid containing steroid hormones, mucopolysaccharides, proteins and FSH in a follicle
GONADOTROPINS!
Early antral follicles depend on FSH to grow normally. As they get larger they will become HIGHLY dependent for growth and viability.
We have now become a early antral follicle.
In the growing antral follicles, what happens to the granulosa cells?
- Increase in number and we get 2 populations
-
Mural granulosa cells become v steriodogenic.
- After ovulation, they stay in the ovary & become corpus luteum
-
Cumulus cells (cumulus oophorous/corona radiata) maintain gap and adhesion junctions with the oocyte.
- At ovulation, they are released with oocyte.
-
Mural granulosa cells become v steriodogenic.
What happens to the gamete in antral follicles?
- Oocyte grows rapidly at first but slows down in larger follicles.
- Oocyte becomes competent. to completes meoisis I at ovulation.
- Larger antral follicles gain meiotitic competence, but are still under arrest d/t elevated cAMP until the LH surge occurs.
Growth during the antral stage becomes responsive to what?
GONADOTROPINS!
Theca cells develop LH receptors and bind LH -> [cholesterol and acetate-> androstenedione and testosterone]
Mural granulosa cells develop FSH receptors and bind FSH -> secrete aromatase
- Aromatose converts androstenedione into 17B-estradiol.
- Will also secrete inhibin in the early follicular phase.
How do we determine our DOMINANT follicle, the one that will undergo ovulation?
Follicles grow, as estrogen is being released into bloodstream
- Increase estrogen levels feedback and tells AP to secrete less FSH and LH.
- D/t decrease FSH, some follicles will undergo atresia
However, in the early follicular phase, follicle with most FSH receptors (most responsive) will continue to grow and become DOMINANT FOLLICLE that will undergo ovulation.
By midcycle, the dominant follicle will become THE _________.
Large preovulatory follicle
*one that will undergo ovulation*
What is the fate of the dominant follicle?
- Dom follicle will continue to release estrogen, making the AP more responsive to GnRH from hypothalamus.
- As the blood estrogen becomes high in blood, estrogen from dom follicle it is now a positive feedback signal to the AP, causing it to increase FSH/LH secretion in response to + GnRH.
- At the same time, thecal and mural granulosa cells undergo lutenization.
- Increase in FSH/LH induces the periovulatory period: a surge of LH/FSH that lasts 32-26 hours before ovulation.
What affect does the LH surge have?
- Causes dominant follicle to rupture, releasing the corona radiata-oocyte complex
- formation of corpus leutem from remaining leutinized thecal cells and mural granulosa cells.
How is the follicle released from the ovary for ovulation during the periovulatory phase?
- Follicle presses against the wall of the ovary to form a bulge called a stigma.
- LH surge causes theca and granulosa cells to release hydrolytic enzymes and inflammatory cytokines -> break follicle wall, tunica albuginea and surface epithelium near the stigma.
- Causes antral cavity is now continous with the peritoneal cavity.
- Cumulus cells detach from granulosa cells and the oocyte is freed.
- D/t LH surge, oocyte released TGF-B, GDF-9.
- Basal lamina of mural granulosa cells degrades and blood vessels and theca cells push into the granulosa cell.
After ovulation, what happens to the remant of the ovarian follicle?
Remnant of the ovarian follicle becomes corpus luteum, made up of luteinzed theca and granulosa cells.
- Goal of the CL cells: make progestins
- Making progestins requires both theca lutein and granulosa lutein cells.
- BOTH cells are close to blood vessels and can take up cholesterol.
- Thecal lutein cells take up cholesterol and make androstenedione -> goes into blood and granulosa lutein cell.
- Granulosa lutein cell ALSO takes up cholesterol and to make progesterone.
- Aromatase is suppressed, so estrogen synthesis decreases!
- Binding of FSH also release of inhibin.
- THESE PROCESSES: feedback of progesterone and inhibin and decrease of FSH/LH release from the AP -> decrease estrogen, making progesterone the dominant hormone.
How long does the corpus luteum live?
14 days: from formation at ovulation -> menstruation,
- UNLESS it rescued by hCG, which orginates in an implanted embryo. Then, it will live until pregnancy.
What is follicular atresia, the PREDOMINANT process in the ovary.
Follicular atresia is the process in the ovary where ovarian follicle is destroyed at anytime during develpoment.
- Granulosa cells and oocytes undergo apoptosis.
- Thecal cells stay alive the repopulate the cellular stroma of the ovary. They keep their LH receptors and can make androgens; make up the interstitial gland of the ovary.
Summary of folliculogenesis.
- Follicular phase involves recruitment and growth. of antral follicles, selection of a dominant. follicle and growth. of it until ovulation
- LH Surge triggers ovulation
- Luteal phase is the hormonal secretion by corpus luteum.
Describe the follicular phase of the ovarian cycle.
Follicular phase occurs is the 1st day of menstruation (menses) -> day 14 (LH surge)
Controlled by hypothalamus, which secretes GnRH, and AP, which secretes LH/FSH.
During first 10 days:
Goal of the follicle cells: make estradiol 17B
Theca cellsdevelop LH receptors and bind LH ->
Make new cholesterol or take up from via LDL/HDL R mediated uptake
Cholesterol àpregnenolone via CYP11A1 àandrostenedione via CYP17.
However, they cannot directly make estrogen because they do not have aromatase.
Granulosa cells develop FSH receptors and bind FSH to make aromatase. However, they are not located near BV and cannot take up cholesterol and do not have 17, 20 desmolase (CYP17)so they cannot make androstenedione.
Thus, androstenedione -> granulosa cell, where aromatase converts it into estradiol 17B -> secreted J
*they will also make inhibin
At the beginning until about day 4, the endometrial cycle is in menses: old endometrial lining (functional layer) is being shed, producing a period.
The high levels of 17B estradiol then promote the proliferative phase of endometrial cycle.
Endometrium thickens, endometrial glands grow and spiral arteries emerge from basal layer to feed functional endometrium.
Also makes cervical mucus more hospitable to incoming sperm.
COMBINED EFFECTS: optimize change for fertilization, which is best on days 11-15.
Days 10-14:
Granulosa cells develops LH receptors and bind LH.
LH causes granulosa cells to make inhibin, which inhibits FSH productionby the gonadotroph.
Follicles grow as estrogen is being released into bloodstream.
High levels of estrogen negatively feedback and inhibit FSH and LH secretion from AP.
D/t decrease FSH, some follicles will stop growing and die off.
However, follicle with most FSH receptors will continue to grow and become DOMINANT FOLLICLE that will undergo ovulation
Dom follicle will continue to release estrogen, making the AP more responsive to GnRH from hypothalamus.
As the blood estrogen becomes high in blood and reaches threshold, HP axis reverses sensitivity to estrogen -> + feedback -> +FSH/LH -> surge of FSH and LH that occurs 32-36 days before ovulation (periovulatory period)
At the same time, theca cells and mural granulosa cells are undergoing lutinization.
Describe the luteal phase of the ovarian cycle
After ovulation, the remnant of the ovarian follicle becomes corpus luteum
During the luteal phase: the remnant of the ovarian follicle -> corpus luteum, made up of luteinized theca and granulosa cells.
Goal of the CL cells: make progestins
Making progestins requires both theca lutein and granulosa lutein cells.
BOTH cells are close to blood vessels and can take up cholesterol.
Thecal lutein cells take up cholesterol and make androstenedione -> goes into blood and granulosa lutein cell.
Granulosa lutein cell ALSO takes up cholesterol and to make progesterone.
Aromatase is suppressed, so estrogen synthesis decreases!
Binding of FSH also release of inhibin.
THESE PROCESSES: feedback of progesterone and inhibin and decrease of FSH/LH release from the AP -> decrease estrogen, making progesterone the dominant hormone.
[High levels of progesterone/low levels of estrogen] signal ovulation has occurred and stimulates the uterus to enters the secretory phase of the endometrial cycle
Secretory cycle: make uterus receptive to fertilization. How?
Inhibits epithelial cell proliferation but promotes proliferation of endometrial stroma -> predicidual cells, which must be prepared to form the decidua of pregnancy, cause menstruation if no pregnancy.
Increase vascularization and glycogen synthesis
Uterine glands secrete more mucus.
As the window for fertilization begins to close: cervical mucus begins to thicken and become less hospitable to sperm
Corpus luteum will be replaced by corpus albicans, which doesn’t make any hormones: causing decrease in estrogen, progesterone and inhibinWhen progesterone and estradiol reaches lowest levels-> zona compacta and zona spongiosa of endometrium sloughs -> menstruation phase of endometrial cycle begins!
Spiral arteries collapse and the functional layer of endometrium comes off.
MARKS BEGINNING OF NEW MENSTRUAL CYCLE
Describe the hypothlamamic pituitary ovarian system
Draw
- Hypothalamus: releases GnRH
- GnRH binds to gonadotrophs on AP
- AP: releases FSH and LH
- LH acts on:
- theca cells in ovaries -> causes release of progestins and androgens
- granulosa cells in ovaries
- FSH acts on
- granulosa cells
- LH acts on:
After being acted on by FSH and LH: granulosa cells release progestins, estrogens, inhibins and activins.
What are the cellular events that result in the synthesis and secretion of gonadotropins?
- GnRH binds to Gq protein -> +PLC pathway -> IP3 and DAG
- IP3 binds to sER and causes Ca2+ to be released
- DAG -> +PKC
- PKC phosphorylates targets that + gene transcription
- LH and FSH a/b dimers. Alpha subunits are the same and B determine if its. FSH or LH
- Gonadotropins are made, dimerized and glycolsylated by rhythm of GnRH.
- Increases intracellular Ca2+ -> +Ca2+ channels -> sustained increase in Ca2+
- Increase Ca2+ causes exocytosis. and release of gonadotropins.
What factors affect the production and secretion of FSH and LH from the AP by turning off PKC gene transcruption?
- During the folicular stage: estrogen stimulates release
- During the luteal phase: estrogen and progesterone inhibit release
- Inhibin inhibits FSH release
- Activin stimulates FSH release
How do pulsitile releases of GnRH change throughout follicular phase?
- Early follicular phase: Burst of GnRH only. causes a. small rise in LH.
- Late follicular phase: High levels of estradoil enhance the sensitivity of gonadotrophs to GnRH -> triggers a much larger release of LH d/t. high. levels. of estradoil.
FSH and LH stimulate ovarian cells to secrete what before and after ovulation?
ESTROGENS AND PROGESTINS
-
Before ovulation: LH and FSH act on cells of developing follicle.
- Theca cells have LH receptors
- Granulosa cells have LH and FSH receptors
- FSH and LH are both needed to make estrogen
- After ovulation: LH acts corpus leutum -> estrogen and progestins.
________ also secrete inhibin and activins, which do what?
OVARIES
Granulosa cells release inhibin (which will inhibit FSH production) when:
- FSH binds
- LH binds to granulosa cells after they get LH receptors, just before ovulation.
Granulosa cells also make activin, which + FSH release.
Describe the negative feedback of the hypothalamic-pituitary-ovarian axis
In most of the cycle (follicular phase and luteal phase), estrogens and progestins exert negative feedback on hypothalamus and AP -> -LH/FSH release.
- -Follicular phase: Estrogens will cause - FB at low and high levels
- -Luteal phase: Progesterone is the primary hormone and exerts - FB only at high levels.
Describe the + feedback of the hypothalamic-pituitary-ovarian axis
At the end of the follicular phase (midcycle), estradiol and progesterone causes + feeback to cause LH surge!
- Estradoil levels rise gradually during 1st half of follicular phase. and steeply 2nd have.
- After estradoil reaches a certain threshold FOR AT. LEAST 2 DAYS, it has + feedback effect on the anterior pituitary -> + FSH and LH -> Surge of FSH and LH -> then triggers ovulation
- Increasing progesterone during late follicular phase also causes + FB and facilitates. with the + feedback
What hormonal changes do we see at. ovulation (when luteal phase BEGINS)?
- Rapid drop in FSH/LH d/t negative feedback of progesterone, estradiol and inhibin
What hormone changes occur during the luteal phase?
- Rise in estradoil, progesterone, and inhibin -> continued -FSH/LH midway through luteal phase. Circulating LH levels fall slowly.
- At the end, the demise of the corpus luteum causes -> decrease levels of progesterone, estradoil and inhibin
After the onset of menstruation, what happens to LH secretion?
Follicular phase pattern of LH secretion (a gradual increase in the frequency of GnRH pulses)
- Estrogens are derived from the _______________________________.
- In a non pregnant woman, _____________ (primary circulating estrogen) is secreted principally by the ovary
- Ovarian cells can synthesize their own _________ de novo
- Estrone can be converted into the more powerful estrogen estradiol, & vice versa – via _________________•
- The ______ can convert both estradiol & estrone into estriol (weaker estrogen)
- Ovary, adrenal glands, peripheral conversion in fat tissue
- Estradiol
- Cholesterol
- 17B-hydroxysteroid DH.
- Liver
During the follicular phase,
What is the major product of the follicles and how do they make it?
Major product of follicles: estrogen.
Making estrogen requires both theca and granulosa cells. Theca cells are close to blood vessels and can take up cholesterol.
- Theca cells take up from blood via cholesterol (LDL/HDL R mediated uptake) -> pregnenolone via CYP11A1 -> androstenedione via CYP17. However, they cannot directly make estrogen because they do not have aromatase.
- Granulosa cells make aromatase. However, do not have 17, 20 desmolase (CYP17) so they cannot make adrostenedione.
- Thus, androstenedione -> granulosa cell, where aromatase converts it into estradiol 17B and secretes it into circulation.
During the luteal phase, the major products of the ____________ are __________.
Does estradoil synthesis still occur?
Corpus lutenum are progestins.
Yes, estradiol synthesis is still substantial
Describe progesterone synthesis in the luteal phase!
Major product of CL: progestin, but estradoil synthesis does occur.
Making progestins requires both theca lutein and granulosa lutein cells. BOTH cells are close to blood vessels and can take up cholesterol.
- Thecal lutein cells take up cholesterol and make androstenedione -> goes into blood and granulosa lutein cell.
- Granulosa lutein cell ALSO takes up cholesterol and to make progesterone.
- However, aromatase is suppressed so we will have a net product of progesterone in the luteal phase!
How do hormones change the lining of the endometrium during the proliferative phase and menstrual phase?
- In proliferative, estrogen will restrore the endometrium.
- 2.In in the menstrual phase, low levels of progesterone and estrogen will destruct the zona compacta and zona spongiosa and endometrium sloughs!
When do we have the highest. levels of estrogen?
Estrogen levels peak just before ovulation. -> LH SURGE
- High levels of estrogen present during the pre-ovulatory (follicular) phase of menstrual cycle ____ basal body temperature.
- Higher levels of progesterone released by BL after ovulation ___ BBT.
Lower
Raise
If pregnancy does not occur, the disintegration of the corpus luteum causes a ______ in BBT that roughly coincides with the onset of the next period
DROP
Describe the menstrual phase of the endometrial cycle
- Menstrual phase occurs if oocyte was not fertilized and pregnancy did not occur, CL degenerates and causes decrease of of estrogen and progesterone -> endometrium degenerates
Describe the proliferative phase of the endometrial cycle
- After menstruation, the proliferative phase occurs and the endometrium begins to become restored by day 5.
- The process is dependent on estrogen, which will also make progestin receptors on endometrial tissue.
- Proliferation of stromal cells (make CT. of endometrium), epithelial cells,
How is the action of progesterone and estrogen different on epithelial cells of the endometrium?
Progesterone opposes the action of estrogen on the epithelial cells of the endometrium by:
- inhibiting epithelial cell proliferation but promotes proliferation of the endometrial stroma
- Stimulates 17β-HSD & sulfotransferase (converts ESTRODIOL ->. weaker. compounds
Describe the secretory phase of the endometrial cycle
Early and middle-late phases.
Secretory phase = luteal phase of ovarian cycle.
Early phase: progesterone develops _nucleolar channel sysyem i_n endometrial epithelial cells
Middle to late. phases:
- Increase in vascularization and glycogen content
- Endometrial glands become engorged with secretions
- Progesterone causes stromal cells -> predecidual cells, which must be prepared to form the decidua of pregnancy, cause menstruation if no pregnancy.
Oral contraceptive pills are taken daily for 21 days out of the 28-day cycle; placebo or iron pill taken during days 22 – 28. What kind do we have?
- Numerous combination (estrogen + progestin) pills
- Progestin only pills
How do OCPs work?
- Estrogen and progestin negatively feedback GnRH secretion of hypothalamus and FSH/LH secretion from AP, causing a net decrease of FSH/LH.
- Low FSH levels-> cannot stimulate folliculogenesis
- Low LH levels -> no LH surge and no ovulation
- Progestin thickens mucus so sperm cannot penetrate.
**In the commonly used doses, contraceptive steroids DO/ DO NOT completely abolish either gonadotropin secretion or ovarian function
DO NOT
What is better: progestin only OCPs or combined?
combined
Disorders of menstruation are common
Include: –
- _____: loss of > 80 mL of blood –
- ______: painful periods –
- ______: existence of few, irregular periods –
- ______: absence of periods
- Menorrhagia: loss of > 80 mL of blood –
- Dysmenorrhea: painful periods –
- Oligomenorrhea: existence of few, irregular periods –
- Amenorrhea: absence of periods
What. is polycystic ovarian syndrome?
PCOS is the most common cause of infertility in F caused by: High LH and testosterone and low FSH.
Cause: hyperandrogenism (cause atresia of follicles), anovulation (no ovulation) and polycystic ovary (causes high DHEA andogen)
presentation of. a. F with PCOS
young
obsese
hirutism
oligomenorrhea
secondary amenorrhea
inferility
What. is the. most common cause of congenital HYPOGONADISM
Turners Syndrome, where 50% of cases are. d/t loss of send X chromosome (45 X)
What is turners syndrome
(45 X) resulting in primary hypogonadism, germ cells do not develop and gonads are CT filled streak.
Internal/external genetilia are. F.
D/t Ovarian failure, many ppl will have HIGH FSH
Presentation of Turners syndrome
short stature,
no secondary sex characterists
webbed neck
square chest.
absence of period
What is menopause
Menopause- no pd for at. least. a. year d/t
[low estrogen and inhibin] -> [high FSH and LH]
