Week 9: Female Reproductive Histo and Menstrual Cycle Hormones

layers of the uterine wall:

*endometrium, myometrium, perimetrium*

corpus luteum becoming corpus albicans

-CL will grow to about 1.5 cm about 7-8 days after ovulation -then the CL will begin to involute -it will eventually lose its secretory function and its yellowish, lipid characteristic about 12 days after ovulation, becoming the corpus *albicans*

Ovulation -What type of oocyte is released?

-SECONDARY oocyte!! (remember, the primary oocyte just finished meiosis I and arrested in metaphase II of meiosis II)

(ppt) *inhibin*

-a peptide hormone secreted by the ovaries -has a negative effect on pituitary FSH

When does the first meiotic division of they oocyte occur?

-after puberty (before then, all oocytes were arrested in meiosis I)

describe the first and second meiotic divisions

-after puberty, each oocyte divides into 2 cells, a large ovum (secondary oocyte) and a small first *polar body* -each of these cells contains 23 chromosomes. The first polar body may or may not undergo a second meiotic division and then disintegrates. -the ovum undergoes a second meiotic division, and after the sister chromatids separate, there is a pause in meiosis.

Advanced atresia:

-atretic follicle is characterized by being surrounded by a *Glassy membrane (GM) = highly thickened basement membrane of GCs and theca interna*

what day of the menstrual cycle does involution occur?

-final involution occurs about 12 days after CL was formed, about the 26th day of the normal cycle -2 days before menstruation

why is cervical mucus less viscous near ovulation?

-less-viscous mucus is more favorable for sperm migration!!

Vaginal *mucosa* -what type of epithelium?

-non-keratinized stratified squamous epithelium + lamina propria (w/ lymphocytes and neutrophils)

*Primordial follicle*:

-oocyte + a single layer of squamous follicular cells -1st appears early in embryonic life -just deep to tunica albuginea

uterine phases (3):

1. Proliferative (follicular) 2. Secretory (luteal) 3. Menstrual

Intracellular mechanism of action of estrogen:

Estrogens can enter cells by diffusion. Bind to receptor (ER). Receptor-ligand complexes bind to EREs. This upregulates or downregulates transcription of specific genes, e.g., upregulate ER and PR.

histology stain of late primary follicle

ZP= zona pellucida GC= granulosa cells

vascularization of the corpus luteum?

a well vascularized supply grown into the corpus luteum

osteoporosis of the bones caused by estrogen deficiency in old age:

after menopause, the estrogen deficiency leads to 1. increased osteoclastic activity in the bones 2. decreased bone matrix 3. decreased deposition of bone calcium and phosphate this is why postmenopausal women used to be treated with estrogen replacement

in what part of the oviduct does fertilization occur?

ampulla / fallopian tube

theca interna: theca externa:

theca interna: -cells have epithelioid characterisitics similar to those of the granulosa cells -ability to secrete steroid sex hormones, *estrogen* and *progesterone* theca externa: -highly vascular CT capsule that becomes the capsule of the developing follicle

structure of ovary: *cortex* cont. -what is deep to the germinal epithelium?

-dense CT called the *tunica albuginea* -cortex is mostly *CT stroma*, except for the follicles -follicles contain the oogonia

corpus luteum: *granulosa cells* -secrete what?

-develop extensive intracellular smooth ER that form large amounts *progesterone* and *estrogen* (with more progesterone during the luteal phase)

(ppt) folliculogenesis -what is follicular atresia due to?

-due to apoptosis, a regulated active process triggered by a cascade of caspase proteases that lead to characteristic fragmentation of DNA, membrane blebing, and cell death

secretory (progestional) phase- this occurs after ovulation

-during most of the latter phase of ovulation, progesterone and estrogen are secreted in large quantities by the corpus luteum -*estrogens*: cause a slight additional cellular proliferation in the endometrium during this phase of the cycle -*progesterone*: marked swelling and secretory development of the endometrium -cytoplasm of the stromal cells increase, lipid and glycogen deposits increase, and the blood supply further increases

involution of the CL and onset of the next ovarian cycle -what hormones have strong feedback effects on the anterior pituitary gland to maintain low secretory rates of FSH and LH? -what causes degeneration of the CL?

-estrogen in particular and progesterone to a lesser extent secreted by the CL -also, the lutein cells secrete small amounts of *inhibin*, which inhibits FSH secretion by the anterior pituitary gland -low blood concentrations of both FSH and LH result, and the loss of these hormones finally causes the CL to degenerate completely (*involution*)

What happens when the tunica albuginea (TA) gets so thick that the follicles can't migrate through it?

-fluid filled cysts and atrophic secondary follicles develop -the thickened TA prevents ovulation → *polycystic ovarian disease*

*Atretic Follicles*:

-follicles that degenerated before they become fully mature -remember, there were millions before birth and even 400-500,000 during puberty -with each ovarian cycle, about 20 follicles start to mature, but only 1 becomes fully developed → the rest undergo *atresia*

*LATE primary follicle*:

-follicular cells become *stratified* cuboidal cells -once they are multilayered, they are called *granulosa cells* -lots of *gap junctions* b/w granulosa cells -*theca folliculi*: CT cells just outside the basal lamina. Flat cells.

corpus luteum: *theca cells* -secrete WHAT hormones? -conversion by WHAT enzyme?

-form mainly the androgens *androstenedione* and *testosterone* rather than the female sex hormones -however, most of these hormones are also converted by the enzyme *aromatase* in the granulosa cells into *estrogens*

what layer of the uterus is sloughed off during menstruation?

-functional layer of endometrium -basal layer of endometrium will be preserved

On what day of the female sexual cycle does ovulation typically occur?

-in a woman who has a normal 28 day cycle, it occurs 14 days after the onset of menstruation

Estrogens increase body metabolism and fat deposition -explain

-increase whole body metabolic rate slightly, but only about 1/3 as much as the increase caused by testosterone -cause deposition of increased quantities of fat in the sub-q tissues → % of body fat in females is greater -besides deposition of fat in the breasts and sub-q tissues, estrogens cause the deposition of fat in the buttocks and thighs

(ppt) Ovulatory cycle: *midcycle peak*

-increased LH and FSH and E2 lead to chemical changes within the ovary that result in dissolution of the follicle wall and ovulation

Major events just prior to ovulation: -liquor folliculi? -____ hormone surge -what happens in the oocyte? -cell-cell adhesions loosened? -what contracts?

-increased hydrostatic pressure of liquor folliculi in antrum -LH surge from pituitary gland -oocyte completes meiosis I, and starts meiosis II, but gets *arrested in metaphase II* → *Secondary oocyte* -proteases from fibroblasts and GAG deposition loosens cell-cell adhesions → frees oocyte and the corona radiata from cumulus oophorus -theca externa cells contract → help expel oocyte and corona radiata for ovulation

effect of estrogens on the skeleton:

-inhibit osteoclastic activity in the bones and therefore *stimulate bone growth* -cause uniting of the epiphyses with the shafts of the long bones → this effect of estrogen in the female is much stronger than the similar effect of testosterone in the male →growth of the female usually ceases several years earlier than growth of the male

First few days of the monthly female sexual cycle CONT. -what is happening during the accelerated growth of these primary follicles?

-initial effect is rapid proliferation of the granulosa cells, giving rise to many more layers of these cells -also, spindle cells from the ovary interstitium collect in several layers outside the granulosa cells, giving rise to layers of *theca* cells

how do follicles move in the cortex during maturation?

-primordial follicles are most superficial, just under the tunica albuginea -as they develop, they migrate more deeply into the CT stroma -eventually will develop into secondary follicles, with a large fluid-filled antrum -as follicle gets ready to ovulate, it will move back to the surface of the ovary where it will release the egg → *"yo-yo" movement*

progesterone promotes secretory changes in the uterus

-promotes secretory changes in the uterine endometrium during the latter half of the monthly female sexual cycle, thus preparing for implantation -decreases the frequency and intensity of uterine contractions, thereby helping to prevent expulsion of the implanted ovum

rate of LH, FSH, estrogen, and progesterone secretion during the last 2 days before ovulation:

-rate of LH secretion by anterior pituitary increases DRASTICALLY (6-10x) -FSH also increases by about 2-3x during this time -FSH and LH act synergistically to cause rapid swelling of the follicle during the last few days before ovulation -LH converts the granulosa and theca cells to mainly progesterone secreting cells → estrogen falls about 1 day before ovulation, while increasing amounts of progesterone begin to be secreted

mature follicle:

-reaches a diameter of 1 to 1.5 cm at the time of ovulation

structure of ovary: *medulla*

-rich vascular bed w/helical arteries -blood, lymph, and nerves enter the cortex at the *hilum*

(ppt) Ovulatory cycle: *follicular phase*

-small and medium sized follicles produce low amounts of E2 -GnRH pulse frequency is every 90 min -FSH is highly glycosylated and elevated → stimulates follicle growth and E2 begins to rise -GnRH pulse frequency increases to every 60 min -LH and FSH potency increases -Increased frequency of GnRH also upregulates GnRH receptors on the anterior pituitary -Near the time of ovulation, E2 is sustained at high levels and this sensitizes the pituitary to GnRH

vaginal *muscularis* -what type of muscle?

-smooth muscle -striated at vaginal opening, though!!

comparative histology of the 3 uterine phases:

-straight uterine glands during proliferative (follicular) phase -coiled glands during secretory (luteal phase)

effect of estrogens on the skin:

-texture that is soft and smooth -skin gets thicker than that of a child or castrated female though -increase vascularization → increased warmth of the skin and greater bleeding of cut surfaces than is observed in men

First few days of the monthly female sexual cycle -concentrations of FSH and LH? -which increase occurs first?

-the concentrations of both FSH and LH secreted by the anterior pituitary increase slightly to moderately, with the increase in FSH slightly greater than that of LH and preceding it by a few days -These hormones, especially FSH, cause accelerated growth of 6 to 12 primary follicles each month

What happens to hormone levels after the corpus luteum has degenerated?

-the sudden cessation of secretion of estrogen, progesterone, and inhibin by the corpus luteum removes the feedback inhibition of the anterior pituitary gland, allowing it to begin secreting increasing amounts of FSH and LH again -FSH and LH initiate the growth of new follicles, beginning a new ovarian cycle -the paucity of secretion of progesterone and estrogen at this time also leads to menstruation in the uterus

image of cyclic changes in the uterine endometrium:

-thickness of endometrial layer changes during menstrual cycle -follicles develop until the graphian follicle ovulates. Then you have the corpus luteum. -right after menstruation, when the functional layer of the endometrium gets sloughed off, endometrium regenerates under the influence of *estrogen*. -endometrium becomes thickened -LH surge comes right before ovulation -after ovulation, there is higher levels of progesterone, made by the granulosa luteal cells and thecal luteal cells -endometrium gets the thickest during the luteal phase

estrogens slightly decrease protein deposition -explain

-this mainly results from the growth promoting effect of estrogen on the sexual organs, the bones, and a few other tissues -the enhanced protein deposition caused by testosterone is much more general and much more powerful than that caused by estrogens

what is the purpose of all of the changes during the secretory (progestational) phase?

-to produce a highly secretory endometrium that contains large amounts of stored nutrients to provide appropriate conditions for implantation of a *fertilized ovum* -this "*uterine milk*" provides nutrition for the early dividing ovum during the 3 days it takes to implant

EM

-upper left corner: part of oocyte -lower right corner: one of the granulosa cells -extending from the oocyte are microvilli (*Mv*) into the ZP -extending from the GCs are cytoplasmic processes (*Pr*) → oocyte and GCs can communicate with eachother

*effect of estrogens on the uterus and external female genitalia*:

-when estrogen secretion increases during puberty, the ovaries, fallopian tubes, uterus, and vagina all increase several times in size -external genitalia enlarge, with deposition of fat in the mons pubis and labia majora and enlargement of the labia minora

After the early proliferative phase of growth, lasting a few days, the mass of granulosa cells secretes a follicular fluid that contains a high concentration of...

.. *estrogen*

Corpus luteum -both the TLCs and the GLCs are now secreting....

.. *progesterone*

Both FSH and LH stimulate their ovarian target cells by ...

.. combining with FSH and LH receptors in the ovarian target cell membranes -in turn, the activated receptors increase the cells' rates of secretion and usually the growth and proliferation of the cells as well

the ovarian changes that occur during the sexual cycle depend completely on...

.. the gonadotropic hormones *FSH* and *LH*, which are secreted by the anterior pituitary -without these hormones, the ovaries remain inactive. This is the case in childhood, when almost no pituitary gonadotropic hormones are released -during puberty, the pituitary begins to secrete progressively more FSH and LH

(ppt) length of menstrual cycle is dependent upon...

.. time required for follicle maturation and the functional life span of the corpus lutem

This accelerated growth is caused by: (3)

1. Estrogen is secreted into the follicle and causes the granulosa cells to form increasing numbers of FSH receptors; this causes a positive feedback effect because it makes the granulosa cells even more sensitive to FSH 2. The pituitary FSH and the estrogens combine to promote LH receptors on the original granulosa cells, thus allowing LH stimulation to occur in addition to FSH stimulation and creating an even more rapid increase in follicular secretion 3. The increasing estrogens from the follicle plus the increasing LH from the anterior pituitary gland act together to cause proliferation of the follicular thecal cells and increase their secretion as well

Direct membrane effects of progesterone and its metabolic products:

Progestogenic neurosteroids interact with GABA and NMDA neurotransmitter receptors on neuronal and glial cell membranes to influence mood and behavior. There may also be a non-classical PR on GnRH neurons and other cells that also respond to circulating progesterone.

If there is no fertilization or pregnancy that takes place, what happens to the corpus luteum?

The corpus luteum will shrink up and become a fibrous mass called the *corpus albicans* -albicans means white body. So it looks white

What is happening in the *transformation zone* of the cervix?

The epithelium changes from *simple columnar* to *non-keratinized stratified squamous* (characteristic of the vagina) epithelium

Initiation of ovulation -what does the LH surge cause to happen?

This LH causes rapid secretion of follicular steroid hormones that contain progesterone. Within a few hours, two events occur, both of which are necessary for ovulation: (1) The theca externa (the capsule of the follicle) begins to release proteolytic enzymes from lysosomes, and these cause dissolution of the follicular capsular wall and consequent weakening of the wall, resulting in further swelling of the entire follicle and degeneration of the stigma. (2) Simultaneously there is rapid growth of new blood vessels into the follicle wall, and at the same time, prostaglandins (local hormones that cause vasodilation) are secreted into the follicular tissues.

What is the purpose of the ZP-3 glycoprotein?

When the sperm get into the female reproductive tract, they can bind to the egg and start fertilization process

*GnIH*

a hypothalamic peptide hormone that acts on the pituitary to decrease gonadotropin secretion from the pituitary GnRH mediates the positive feedback effect of E2; GnIH mediates the negative effects upstream to GnRH GnIH also acts at the level of the ovaries and testes in an autocrine/paracrine fashion to regulate oogenesis and spermatogenesis, slowing down gamete proliferation and maturation

accumulation of these fluid causes WHAT to appear?

an *antrum* appears

estrogen effects in the uterine endometrium during puberty:

cause marked proliferation of the endometrial stroma and greatly increased development of the endometrial glands, which will later aid in providing nutrition to the implanted ovum

effect of estrogens on electrolyte balance

cause sodium and water retention by the kidney tubules slight are rarely of significance, but during pregancy, the tremendous formation of estrogens by the placenta contributes to swelling

follicles in different stages of maturation are found in what layer of the ovary?

cortex!

Extracellular mechanism of action of estrogen:

estrogens can also bind to ER and heterologous receptors in the plasma membrane These actions are mediated through kinase activated signal transduction pathways. These effects may be rapid.

how do estrogens change the vaginal epithelium during puberty?

from a cuboidal into a stratified type, which is considerably more resistant to trauma and infection than is the prepubertal cuboidal cell epithelium

Why is the process of atresia important?

it normally allows only one of the follicles to grow large enough each month to ovulate this usually prevents more than one child from developing each pregnancy

the early growth of the primary follicle up to the antral state is stimulated mainly by WHAT hormone alone?

mainly by *FSH*

cyclic changes in uterine glands during ovarian follicular vs luteal phases: -what hormone is high during each phase? -edema occurs in the lamina propria in WHAT phase?

ovarian FOLLICULAR phase (proliferative phase of uterus): -*estradiol* is high -uterine glands tend to be pretty straight and compact ovarian LUTEAL phase (secretory phase of uterus): -higher *progesterone* than estradiol -glands become coiled -lamina propria becomes filled with fluid → cushy surface for an implanting embryo

progesterone promotes development of the breasts

promotes development of the lobules and alveoli of the breasts, causing the alveolar cells to proliferate, enlarge, and become secretory however, does not caues the alveoli to secrete milk; milk is only secreted after prolactin stimulation also causes breasts to swell

effect of progesterone on the fallopian tubes

promotes increased secretion by the mucosal lining of the fallopian tubes secretions are necessary for nutrition of the fertilized, dividing ovum as it traverses the fallopian tube before implantation

what is menstruation due to?

reduction of estrogens and progesterone, especially progesteron, at the end of the monthly ovarian cycle

what happens to the corpus albicans?

replaced by CT and over months is absorbed

stigma: -what happens shortly before ovulation?

shortly before ovulation the protruding outer wall of the follicle swells rapidly, and a small area in the center of the follicular capsule, called the stigma, protrudes like a nipple in another 30 min or so, fluid begins to ooze from the follicle through the stigma, and about 2 min later, the stigma ruptures widely, allowing a more viscous fluid, which has occupied the central portion of the follicle, to evaginate outward. this viscous fluid carries with it the ovum surrounded by the *corona radiata*

After ovulation what occurs

the empty follicle becomes rapidly vascularized due to angiogenic factors including VEGF and bFGF, forming the CL. Increased vascularity facilitates delivery of LDL cholesterol substrate for prodigious amounts of steroidogenesis. LH or hCG can prevent the demise of the CL. Otherwise the normal life span of the CL is 14 2 days.

postulated cause of atresia:

the large amounts of estrogen from the most rapidly growing follicle act on the hypothalamus to depress further enhancement of FSH secretion by the anterior pituitary gland, in this way blocking further growth of the less well developed follicles therefore, the largest follicle continues to grow because of its intrinsic positive feedback effects

what do the granulosa cells in the primordial follicle do during childhood? What happens after puberty?

they provide nourishment for the ovum and secrete an *oocyte maturation-inhibiting factor* that keeps the ovum suspended in its primordial state in prophase I -after puberty, FSH and LH are secreted in significant quantities -the ovaries, along with some of the follicles inside, begin to grow

In a healthy ovary, the structure just deep to the germinal epithelium is the...

tunica albuginea lies just beneath the germinal epithelium, right before you get to the primordial follicles

What type of epithelium does the oviduct mucosa have? -changes during the follicular vs luteal phases

*simple columnar epithelium* -*follicular phase*: hypertrophy and ciliogenesis -estrogen is high during follicular phase -cilia beat oocyte down the oviduct -*luteal phase*: atrophy

After the antral state, greatly accelerated growth occurs, leading to still larger follicles called

*vesicular follicles*

What is the glycogen found in these cells for?

-Bacteria convert glycogen→lactic acid -this lowers the pH and increases the acidity of the mucosal lining -most acidic at mid-cycle (during ovulation) -this inhibits pathogenic invasion; good time to get pregnant

What is the clinical significance of the histological change between the cervix and vagina?

-Pap smears are taken from the transformation zone, because this is where the vast majority of neoplasias occur that can lead to cervical cancer.

There continues to be a collaboration after ovulation, now between the thecal lutein cells and the granulosa lutein cells EXPLAIN

-TLCs transport the steroid precursor (androstenedione) to the follicular lutein/granulosa lutein cells (GLCs) -LH causes the cells to make not only estradiol, but *progesterone* → high levels of progesterone after ovulation Cholesterol is taken up from the blood and used to synthesize progesterone by follicular lutein cells.

*Graafian Follicle* -antral cavity? -corona radiata? -what receptors begin to be expressed?

-antral cavity becomes very enlarged -whole follicle is moving towards surface of ovary, getting ready to ovulate -the granulosa cells around the oocyte will be expelled with the oocyte at ovulation; will become the *corona radiata* -*LH receptors* are expressed on granulosa cells (FSH receptors are already present) -*Cumulus Oophorus (CO)*: mound of granulosa cells that attach oocyte to the wall of the follicle

*Secondary (Antral) Follicle* -what is the antrum? -layers of GCs? -primary oocyte size?

-as more fluid is secreted, the spaces between the GCs coalesce into an *antrum* -antrum: cavity filled w/ fluid (*liquor folliculi*: GAGs, steroids, growth factors, gonadotropins) -GCs develop many many more layers -a *theca externum* develops -primary oocyte becomes even larger

structure of the vagina:

-collapsed fibromuscular sheath, not a rigid tube

Corpus luteum- the *luteal phase* of the ovarian cycle -luteinization?

-during the first few hours after expulsion of the ovum from the follicle, the remaining graulosa and theca interna cells change rapidly into *lutein cells* -they enlarge in diameter and become filled with lipid inclusions that give them a yellowish appearance → *luteinization*

cervical glands -function:

-mucus-secreting -lubricate the vagina -mucus is thick except at mid-cycle. Less viscous near ovulation

micrograph of primary oocyte in secondary follicle:

-not seeing the whole antral cavity in this pic -still have primary oocyte arrested in prophase I

Structure of ovary: *cortex* -outside is covered by... -site for the most common type of ovarian cancers?

-on outside is covered by a *mesothelium* that is continuous with peritoneal cavity -mesothelium was given the name *"germinal epithelium"* because researchers thought that;s where the eggs came from... Turns out they come from the embryonic yolk sac and then migrate in to what will become the ovary -germinal epithelium is the site of the most common type of ovarian cancers

Vagina -layers

-outer *adventitia*; numerous elastic fibers -middle *muscularis* -inner *mucosa* (facing lumen)

(ppt) Folliculogenesis -are pre-antral vs post-antral follicles and their dependence on gonadotropins

-pre-antral follicles can be viewed as gonadotropin independent -antrum formation and follicle maturation require FSH. Late luteal FSH rescues a cohort of developing follicles from atresia, eventually allowing a dominant follicle to emerge

Phases of endometrial cycle

-proliferative phase (estrogen phase) -secretory phase (progestinal phase) -menstruation

*luteinizing function of luteinizing hormone*

-the change of granulosa and teca interna cells into lutein cells is dependent mainly on LH secreted by the anterior pituitary gland (this is the function that gives LH its name)

3 distinct regions of the cervix:

1. *endocervical canal* 2. *transformation zone* 3. *ectocervix*

4 anatomical subdivisions of the oviduct (*fallopian tube, uterine tube*):

1. *infundibulum* w/ fimbriae -fimbriae sweep fluid from peritoneal cavity and oocyte, once its ovulated, into the oviduct 2. *ampulla* -longest portion 3. *isthmus* 4. *intramural* -penetrates the thick uterus wall

Cyclical vaginal epithelial changes:

After ovulation, *estrogen is LOW* = -lining of the vagina is not as thick During the first part of the menstrual cycle and before ovulation, *estrogen is HIGH* = -thicker stratified squamous epithelium -cells have *glycogen inclusions*

Intracellular mechanisms of progesterone:

Enters cell by diffusion. Binds to receptor (PR). Receptor-ligand complexes bind to PREs. Binding to PRE affects gene transcription, e.g. downregulates ER and PR.

labeled stain of secondary (antral) follicle

GC = granulosa cells TE = theca externa cells TI = theca interna cells A = antrum

LH Effects

LH stimulates the theca cells of the ovarian follicle to produce androgens. Aromatase within the follicles granulosa cells subsequently converts these androgens to estradiol under FSH stimulation. The theca externa cells serve as a connective tissue support structure of the follicle.

a surge of ____ is necessary for ovulation -describe

LH!! -LH is necessary for final follicular growth and ovulation -without this hormone, even when large quantities of FSH are available, the follicle will not progress to the stage of ovulation

(ppt) How does the uterine cycle correspond to the ovarian cycle?

The uterine *proliferative phase* corresponds to the ovarian *follicular phase*. Under the influence of estradiol, the uterine endometrial cells proliferate. The uterine *secretory phase*, after ovulation, corresponds to the ovarian *luteal phase*. During this phase the endometrial cells enlarge and form secretory glands. In the absence of fertilization the uterine lining enters the degenerative phase. Prostaglandins lead to vasomotor reactions, endometrial ischemia and reperfusion injury, resulting in necrosis and loss of the endometrial lining.

what do these 2 effects cause to happen?

These two effects cause plasma transudation into the follicle, which contributes to follicle swelling. Finally, the combination of follicle swelling and simultaneous degeneration of the stigma causes follicle rupture, with discharge of the ovum

how are estrogens and progesterone transported in the blood?

bound to plasma proteins, mainly plasma albumin and with specific estrogen and progesterone binding globulins the binding is loose enough that they are rapidly released to the tissues over a period of 30 min

image of the pulsatile release of GnRH and LH -when is FSH high vs LH in regards to pulse frequency?

different frequencies of GnRH pulses can lead to differential ratios of LH and FSH secrtion -high frequency: high LH -low frequency: high FSH

follicular vs luteal phase

follicular: before ovulation luteal: after ovulation

*oocyte maturation inhibitor*:

secreted from GCs keeps oocyte arrested in prophase I

peg cells: -what hormone increases the #?

secretory cells secrete nutrients for the oocyte as its making its way down the oviduct -progesterone increases the # of peg cells!

What are *cortical granules*?

secretory vesicles that contain proteases which get exocytosed when the oocyte is fertilized. These proteases degrade sperm-binding receptors on the oocyte's plasma membrane to prevent other sperm from fertilizing the ovum; that is, they block polyspermy.

*perivitelline space*

space between the zona pellucida and the oocyte. this space is made when fertilization takes place.

oogenesis:

the series of steps of a developing egg (oocyte) differentiating into a mature egg (ovum)

which cells are the steroid secreting cells?

theca interna cells

What does the follicle become after ovulation?

*corpus luteum*: what the granulosa cells are called after ovulation name given to a follicle after ovulation because of its yellow color

The granulosa cells in the Graafian follicle will be called WHAT after ovulation?

*granulosa lutein cells*

summary of the effect of estrogens on the breasts:

*initiate growth of the breasts and of the milk-producing apparatus.* *also responsible for the characteristic growth and external characteristic growth and external appearance of the mature female breast* however, do NOT complete the job of converting the breasts into milk-producing organs

uterine gland changes: -proliferative vs early secretory vs late secretory phases

*proliferative phase*: straight tubules; no secretion *early secretory phase*: coiling; glycogen accumulates in BASE of the cells lining the uterine glands *late secretory phase*: highly coiled; more dialated; glycogen secretion from APEX of the cells lining the uterine glands (the simple columnar epithelial cells (magnified) that line the lumen of the uterine glands are shown beside each gland)

*Corpus albicans* -how does the # in the ovary change over time?

-# in an ovary increases with age -macrophages in the CT stroma help to chew up the degenerating cells -So, the corpus albicans was a mature graafian follicle that ovulated an oocyte and then degenerated after that

Microcirculation in the uterus

-*arcuate artery* → *straight/radial artery*(supplies base of gland) AND *helical/spiral artery* (continue up into functional layer; involved in menstruation)

uterine glands -what cells form the glands? -2 layers of the endometrium?

-*simple columnar* cells dip down to form long tubular glands called uterine glands -endometrium has 2 layers: 1. *superficial, functional layer* -contains the majority of the gland 2. *basal layer* -contains the bases of the glands

# of oogonia/oocytes

-5-6 million oogonia/ovary produced early during embyronic development -1-2 million primordial follicles (little pockets that contain the oogonia) at birth; follicles contain primary oocytes arrested in prophase meiosis I -4-500,000 primordial follicles at puberty (the rest have degenerated) -only 400-500 are actually ovulated during the reproductive years

when does the final step in meiosis occur?

-After ovulation and if the ovum is fertililized, the final step in meiosis occurs -half of the sister chromatids in the ovum stay in the fertilized ovum and the other half are released in a second polar body, which then disintegrates

(ppt) Ovulatory cycle: *luteal phase*

-CL secretes large amounts of progesterone and lesser amounts of estradiol -negative steroid feedback at the hypothalamus and pituitary leads to decreased GnRH pulses (100 minutes) and decreased pituitary LH pulse frequency -in the late luteal phase, GnRH pulse frequency is every 200 min -decreased progesterone from the regressing CL leads to menstruation -decreased negative feedback by progesterone (P4) and E2 also results in a gradual rise in LH and FSH

2219. Describe how the hypothalamic-pituitary axis influences the ovarian and uterine components of the menstrual cycle.

-Hypothalamic hypophysiotropic hormones act on cells of the anterior pituitary. Both releasing (e.g., GnRH) and inhibiting factors (e.g., GnIH) regulate the secretion of gonadotropins. -Gonadotropin releasing hormone (GnRH) stimulates release of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH). -GnRH is secreted in a pulsatile fashion from many synchronized GnRH neurons.

Thecal and follicular cells have to cooperate during synthesis of ovarial hormones

-LH will act on the theca interna cells, stimulating them to secrete androgens -androgens will get handed off to the follicular or granulosa cells -the GCs have an enzyme called *aromitase* that converts the androgen precursors into *estradiol*

*Secretion by the corpus luteum: an additional function of luteinizing hormone*

-Once LH (mainly that secreted during the ovulatory surge) has acted on the granulosa and theca cells to cause luteinization, the new *lutein cells* go through a sequence of: 1. proliferation 2. enlargement 3. secretion 4. degeneration -the CL secretes large amounts of both progesterone and estrogen

What is happening histologically during the menstruation phase?

-Periodic contractions of spiral arteries → endometrium is not getting it's regular blood supply → ischemia in functional layer -Spiral arteries break apart. Cells die and slough off -Glands stop secreting (normally secret a lot of glycogen for fertilized egg)

*Corpus luteum* -what does the antrum become filled with? -what do the theca interna cells become? -what do the granulosa cells become?

-The BV that were in the theca interna invade granulosa cells, filling the antral cavity with blood -theca interna cells shrivel up → *theca lutein cells (TLC)* -granulosa cells are now called *granulosa lutein cells (GLC)* (arrows in image point to folds containing TLCs)

*primary follicle* -follicle cells? -zona pellucida? -size of oocyte?

-as the follicle developments, the single layer of flat cells become more *cuboidal* -the cuboidal follicular cells start to express *FSH receptors* -FSH from pituitary gland will be carried through the bloodstream and will bind to these receptors and stimulate the growth -the oocyte will be secreting proteins, glycoproteins, and GAGs. Will accumulate to form the *zona pellucida* -one of the proteins is called *ZP-3* and has the capability to bind *spermatozoa* -the oocyte has become larger.

proliferative (estrogen) phase

-at the beginning of this phase, only a thin layer of endometrial stroma remains -under the influence of *estrogens*, secreted in increasing quantities by the ovary during the first part of the monthly ovarian cycle, the stromal cells and the epithelial cells proliferate rapidly -endometrial glands, especially those in the cervical region, secrete a thin mucus -mucus strings align themselves along the cervical canal, forming channels that help guide sperm into the uterus

(ppt) LH and FSH

-both are heterodimers composed of a common alpha subunit but have a differing beta subunit -stimulate ovarian steroidogenesis and oogenesis

effect of estrogens on the fallopian tubes

-cause glandular tissues of the fallopian tuves to proliferate -increase the number of cililated epithelial cells that line the tuvues -activity of the cilia is considerably increased. Cilia always beat toward the uterus

*primary oocyte*:

-contained inside the primordial follicle -large cell -arrested in *prophase of meiosis I* -large eccentric euchromatic nucleus -1 or more large nucleoli

Negative and Positive feedback by ovarian steroids:

Steroid hormone receptors are abundant in the hypothalamus, on GnRH neurons and many neural systems that impinge on GnRH neurons. At the hypothalamus, E2 and P4 act to slow down the frequency of GnRH release into the portal system. In primates, including humans, there is considerable feedback of estradiol at the pituitary, but most of the P4 feedback is at the level of the hypothalamus. Negative feedback by E2 also occurs through interneurons such as GABA. Negative feedback also occurs at the pituitary directly to decrease LH and FSH synthesis and release and to decrease pituitary sensitivity to GnRH.

effect of estrogens on the breasts: (3)

1. development of the stromal tissues of the breasts 2. growth of an extensive ductile system 3. deposition of fat in the breasts the lobules and alveoli of the breasts develop to a slgiht extent under the influence of estrogens alone, but it is progesterone and porlactin that play the main role

(ppt) 2 major functions of ovary:

1. generation of fertilizable ovum 2. preparation of the endometrium for implantation through sequential secretion of estradiol (E2) and progesterone (P4)

So, environment conditions during ovulation:

1. rapid growth of follicle 2. diminishing estrogen secretion after a prolonged phase of excessive estrogen secretion 3. initiation of secretion of progesterone without the initial LH surge though, ovulation will not take place

does the vaginal mucosa have glands?

NO -remember, lubricated by the *cervical glands*

do estrogens affect hair distribution?

NO. they have little effect the pubic hair that develops after puberty is mainly due to the androgens formed in increased quantities by the female adrenal glands after puberty

how many follicles fully mature each month?

ONLY 1... the reset undergo atresia

Secondary (Antral) Follicle -theca *interna* vs *externa*

*Theca interna*: -highly vascularized cuboidal cells -synthesize & secerete *androgens* due to the influence of LH -have *LH receptors* *Theca externa*: -outer CT cells, smooth muscle, collagen Both are outside basal lamina!!!