13) Female Reproductive Endocrinology Flashcards
What occurs in terms of germ cell development to form oocytes?
- Mitosis of oogonia
- Meiosis I to form oocytes
What phase of meiosis do oocytes remain in until ovulation?
Prophase I
Oocytes are surrounded by what to form a primary follicle?
Single granulosa cell layer
How does male and female germ cell development differ?
- Males: spermatogonia are laid-down during embryogenesis, but are only activated during puberty
- Females: all oocytes are produced during in-utero development, but they are not complete until ovulation and fertilization
How are oocytes lost during in-utero development?
- May not progress through meiotic prophase
- May not successfully be enclosed in a follicle
How many oocytes are present at birth and puberty? How many ovulations occur in a lifetime?
- Birth: 1.5 million
- Puberty: 300 000
- 400 to 500 ovulations in a lifetime
What occurs in terms of the oocytes until puberty?
Waves of follicular growth and atresia
What layer do granulosa cells form? What is its function? When does it develop?
- Corona radiata
- Provides nutrition for the cell
- Develops during the 5th month of in-utero development
What occurs to granulosa cells once ovulation occurs?
They are removed
Why is a larger follicle cell mass desirable?
To allow the fingers of the oviduct to pick up the cell with ease
Where are thecal cells situated? Where are granulosa cells situated?
- Thecal cells are on the outside of the basement membrane
- Granulosa cells are on the inside of the basement membrane
What is the corpus luteum responsible for if fertilization occurs?
The production of progesterone
What occurs to the corpus luteum if fertilization fails?
Luteolysis
Which gonadotrophin do thecal cells respond to? What is the response?
- LH
- Formation of testosterone
Which gonadotrophin do granulosa cells respond to? What is the response?
- FSH
- Formation of estradiol from the testosterone produced in the thecal cells
The antrum of a follicle is high in _________.
estradiol (E2)
The estradiol produced by granulosa cells may affect which tissues?
- Brain (libido and sexual behaviour)
- Reproductive tract
What is the importance of the high estradiol within the antral follicle?
Estrogen is a powerful mitogen
_______ cells provide androgens to _______ cells.
thecal
granulosa
_______ cells produce the circulating estrogens that inhibit the secretion of GnRH, LH, and FSH.
Thecal cells
Inhibin from __________ cells inhibits FSH secretion.
granulosa
LH regulates the ________ cells, whereas __________ cells are regulated by both LH and FSH.
thecal
granulosa
When does estrogen and progesterone exert a positive feedback on the hypothalamus and anterior pituitary?
Days 12 to 14
What produces inhibin A?
Dominant follicle and corpus luteum
What produces inhibin B?
Small follicles
When is inhibin A produced? When is inhibin B produced?
- Inhibin A: luteal phase
- Inhibin B: follicular phase
What is the inhibin receptor?
- There is no specific receptor for inhibin
- Inhibin acts by inhibiting activin
What are the three phases to the follicular wave? How does the quantity of estradiol produced differ between the stages?
1) Recruitment (low E2)
2) Selection (medium E2)
3) Dominance (high E2)
What is recruitment?
- Small antral follicles are recruited
- Entry into gonadotrophin sensitive pool
What is selection?
- Follicles are selected from previously small follicles
- Ovulatory follicles emerge
- They either undergo atresia or develop further
What is dominance?
Selected follicles will ovulate
What are the levels of FSH, LH, inhibin, and estradiol during recruitment?
- High FSH
- Low LH
- No inhibin
- Low estradiol
What are the levels of FSH, LH, inhibin, and estradiol during selection?
- Low FSH
- Moderate LH
- Low inhibin
- Medium estradiol
What are the levels of FSH, LH, inhibin, and estradiol during dominance?
- Low FSH
- High LH
- High inhibin
- High estradiol
How many follicular waves occur during the follicular phase of the reproductive cycle? What do minor waves produce?
- More than one follicular wave typically occurs
- Minor waves do not result in ovulation
At which phase is FSH at its lowest point? Why?
- Selection
- The production of inhibin and estradiol inhibit FSH secretion
Estradiol exerts a positve feedback on the ______ center.
surge
The _____ center is ONLY associated with ovulation, while the ______ center is associated with other reproductive functions.
surge
tonic
What occurs to the surge center after estrogen reaches a threshold level?
Releases high amplitude, high frequency pulses of GnRH in a relatively short period of time
Why does ovulation require the rupture of healthy tissue at the surface of the ovary?
Because there are tissue layers in between the location of the oocyte and the outside of the ovary
Which tissue layer contains the oocyte prior to ovulation?
Theca externa
What are the cellular components of the oocyte at time of ovulation?
- 60-70 times larger than a typical cell
- 100 000 mitochondria
- 100 million ribosomes
- 50 times the ATP
How does the pre-ovulatory surge affect PGF2a?
Increase
What are the effects of an increase in PGF2a following the pre-ovulatory LH surge?
- Increased contraction of ovarian smooth muscle (increases follicular pressure)
- Release of lysosomal enzymes (follicle wall weakens)
How does the pre-ovulatory LH surge affect hormone secretion by the dominant follicle? What is the effect?
- Shift from estradiol to progesterone
- Increase in collagenase, which allows for the weakening of the follicle wall
What is the effect of an increase in PGE2 due to the pre-ovulatory LH surge?
- Increased blood flow to the ovary and dominant follicle
- Edema, which increases follicular pressure
When does meiosis I occur in the oocyte? When does meiosis II occur?
- Meiosis I: ovulation
- Meiosis II: fertilization
What three factors allow for the onset of ovulation?
- Elevated blood flow
- Breakdown of connective tissue
- Ovarian contractions
What do theca interna and granulosa cells become after ovulation?
Form the corpus luteum
How is the tonic center related to the corpus luteum?
- The tonic center produces low levels of GnRH to maintain basal levels of LH
- Stimulates the corpus luteum to secrete mainly progesterone
What is the effect of progesterone produced by the corpus luteum on the hypothalamus?
- Negative feedback on the GnRH neurons of the hypothalamus
- GnRH, LH, and FSH are suppressed and little estrogen is produced
What is the effect of progesterone produced by the corpus luteum on the tonic center? How does that affect the frequency and amplitude of GnRH?
- Reduces the frequency of the pulse
- Amplitude is still relatively high
- Allows follicles to grow, but not mature
What is the effect of progesterone produced by the corpus luteum on the mammary gland?
Positive feedback that promotes alveolar development
What is the effect of progesterone produced by the corpus luteum on the uterine tissue?
- Positive influence on the endometrium
- Inhibits the contraction of the myometrium
- “Progesterone block of pregnancy”
Describe the mechanism by which the luteolytic pathway is activated.
Oxytocin produced by the ovary binds to receptor and activates the synthesis of PGF2a
What are the functions of PGF2a in luteolysis? (3)
1) Increases intracellular calcium, which has apoptotic effects
2) Activates PKC, which inhibits progesterone synthesis
3) Sustained vasoconstriction, causing the endometrial lining to slough off
Describe the phases of the uterine cycle, and the days they correspond to.
1) Menstruation (1-3)
2) Proliferative phase (3-14)
3) Secretory phase (14 to 28)
How do progesterone and estradiol concentrations vary during luteolysis?
Decrease dramatically
When may hCG be detected?
6 to 12 days after fertilization
hCG has the same alpha chain as which hormones?
- FSH
- LH
- TSH
What is the function of hCG?
Stimulates the corpus luteum to maintain steroids until feto-placental unit takes over
Why may the ovaries be removed after the first trimester of pregnancy with no effect?
The placenta takes over the production of the fetus after the first trimester
How do the levels of hCG vary as pregnancy progresses?
- Extremely high levels during the first three months
- Rapid drop after the end of the first trimester
How do the levels of estrogen and progesterone vary as pregnancy progresses?
Increase as pregnancy progresses
The follicular phase is characterized by effects of which hormone?
Estrogen
The luteal phase is characterized by effects of which hormone?
Progesterone
How does the pH vary between the follicular and luteal phase? Why?
- Follicular phase: high pH conductive to sperm survival
- Luteal phase: low pH inhibiting sperm survival
In which structure does the fertilization of the ovum occur?
Oviduct
What is the mechanism by which fertilization occurs?
- Hydrolytic enzymes in the acrosome of the sperm loosen the corona radiata cells around the ovum
- One sperm penetrates and fertilizes the oocyte
What allows for the movement of the ovum along the oviduct to the uterus?
Ciliated cells
What does the fertilized ovum derive energy from prior the implantation in the uterine endometrium?
Oviductal and uterine secretions
How does high estrogen during ovulation affect the oviduct?
- Fimbriae become much more active (easier to grasp egg)
- Local edema and constriction of the oviduct
What is the function of the local edema and constriction of the oviduct?
- The point where fertilization occurs
- Restricts movement of the fluid (containing sperm) past the junction point
- Allows the ovum to meet the sperm at the junction
What is the function of trophoblasts?
Accomplishes implantation and develops into fetal portions of the placenta
What is the function of embryoblasts?
Cells that are destined to become the fetus
What occurs to the restriction point after fertilization? Why?
- Restriction point no longer exists, allowing for the passage of the fertilized ovum along the oviduct
- Due to the increase in progesterone
How do oral contraceptives affect estrogen and progesterone concentrations?
- Maintenance of high levels of progesterone (and estrogen, if combined)
- Maintaining an artificial corpus luteum
What are the two consequences of consistently high levels of estrogen and progesterone in terms of fertility?
- Inhibit the ovulatory surge and follicular development
- Cause the thickening of the mucosa and increased secretions, inhibiting sperm motility
How does the IUD function?
- Blocks the sperm from reaching the oviduct
- Slow release of synthetic progesterone (suppress ovulation)
How long does a progesterone injection last?
3 months
Is combined (estrogen and progesterone) or progesterone therapy alone more effective in terms of birth control?
Progesterone only is slightly less effective
How long does a progesterone implant last?
5 years
What does the Plan B pill utilize?
Synthetic progesterone
When should the Plan B pill be utilized?
Up until 72 hours after unplanned intercourse or suspected contraceptive failure
What is the mechanism of action of the Plan B pill?
- High levels of progesterone may inhibit ovulation and/or ovum/sperm transport and implantation
- Reduces the risk of unplanned pregnancy
What has Health Canada recently stated in terms of the Plan B pill?
These pills are less effective in women weighing 75 to 80 kg, and not effective in women over 80 kg
What pharmaceutical products induce abortion?
- Anti-progesterones
- E.g. RU486
What is the mechanism of action of the progesterone antagonist, RU486?
The receptor complex binds, but gene(s) are not activated
What is the mechanism of action of the progesterone antagonist, ONA?
The receptor complex does not bind
How does RU486 act to induce abortion?
1) Breakdown of the blastocyst
2) Decrease in hCG and progesterone synthesis by the corpus luteum
3) Detachment of the blastocyst
4) Uterine contractions stimulated by prostaglandins act to destabilize the blastocyst and the endometrium
Which chromosome does the placenta of a daughter always express?
The maternal X-chromosome
Which X chromosome do tissues of a daughter express?
- Mosaic tissues
- X-silencing occurs later in development, and is random (mother or father’s X chromosome)
How long is the ovary required during pregnancy? Why?
- 2.5 months
- hCG secreted by the placenta maintains the integrity of the corpus luteum in the ovary until the feto-placental unit takes over
After implantation, the blastocyst develops into a _________, and secretes ____.
trophoblast
hCG
How does hCG affect LH and FSH? Why?
- hCG maintains steroid production by the corpus luteum
- Suppresses LH and FSH
What does the placental unit produce at 9 weeks? What is it converted to?
- Pregnenolone
- Converted to progesterone and DHEA by the fetal androgen gland
What happens to the DHEA produced by the fetal adrenal gland?
Converted to various estrogens by the placenta
How do estriol, estrone, and estrogen compare in terms of potency?
Estriol (E3) is a weaker estrogen than estrone (E1) and estrogen
Which particular estrogen increases during pregnancy?
Estriol (around 1000X the maximum pre-pregnancy values)
Rising levels of which hormone in the blood and urine are the best indicator of “health” of the fetal placental unit and metabolism of the fetus?
Estriol (E3)
How does the output of progesterone and estrogen by the feto-placental unit vary throughout pregnancy?
Continuously increases
What contributes to the progesterone in maternal circulation during pregnancy?
Synthesis by the placenta (week 9)
What contributes to the estrogen in maternal circulation during pregnancy?
Synthesis of DHEA in the fetal adrenal gland, and conversion to estrogen by the placenta
Which estrogens does DHEA produce?
- Estrone (E1)
- Estradiol (E2)
Which estrogen does 16-hydroxy-DHEAS produce? When?
Estriol (E3) at week 12
When do changes in the breast occur in terms of puberty?
Two years before the end of puberty
What does estrogen stimulate in terms of breast development?
- Duct formation
- Accumulation of fat
The effect of estrogen on the breast (increases/decreases) during pregnancy.
increases
Which hormones induce enzymes necessary for milk production during pregnancy? (3)
- Glucocorticoids
- Prolactin
- Placental lactogen
What inhibits milk production during pregnancy?
The high concentrations of estrogen and progesterone
How does milk production occur after parturition?
- Estrogen and progesterone levels fall
- Prolactin stays high
What prevents ovulation during nursing?
High prolactin prevents normal cycling of GnRH
How does the fetal placental unit manipulate the maternal host?
Via output of polypeptide and steroid hormones, resulting in physiological changes in virtually every maternal organ system
How does pregnancy affect the cardiovascular system?
- Increase in heart rate
- Increase in cardiac output
How does pregnancy affect the respiratory system?
Increase in tidal volume
How does pregnancy affect the gastrointestinal system?
- Increased gastric emptying time
- Decreased sphincter tone
How does pregnancy affect the renal system?
Increase in renal flow and GFR
When does the placenta start producing increasing levels of CRH? Until when? What does it stimulate?
- From week 28 to delivery
- Stimulates ACTH from the fetus to increase cortisol
What does estrogen stimulate during parturition due to an increase in cortisol? (2)
- Increased secretion by the uterus (lubrication)
- Increased myometrial contractions
What does PGF2a stimulate during parturition due to an increase in cortisol? (2)
- Luteolysis
- Myometrial contractions
What does relaxin stimulate during parturition due to an increase in cortisol?
Pelvic ligament stretching
What are the effects of myometrial contractions during parturition?
- Increased pressure
- Increased cervical stimulation
- Increased oxytocin
What injuries are more painful than parturition?
- Amputation of a digit
- Causalgia (burning pain after partial injury of a nerve)
When do maternal steroids return to normal levels following parturition?
Within 1 to 3 days
How does the pituitary gland vary during pregnancy? When does it end? Why?
- Increases by about 1/3
- Does not decrease until lactation ends
- Increase in pituitary lactotrophs to support milk production
What prevents ovulation after parturition? When does the normal cycle resume?
- Prolactin suppresses FSH/LH secretion and prevents ovulation
- The normal cycle resumes after lactation (17 weeks)
When is there a sudden drop in the number of follicles in women?
37 years old
What would happen if the rate of follicular atresia remained the same throughout the life cycle?
There would be enough eggs until 71 years old
How do steroid hormones vary after menopause? How do pituitary hormones vary after menopause?
- Decrease in steroid hormones
- Increase in FSH and LH
Why is there an increase in GnRH, LH, and FSH after menopause?
Because there is reduced negative feedback
What are menopausal symptoms that may be treated with estrogen?
- Vasomotor
- Urogenital atrophy
- Osteoporosis
- Psychosocial (insomnia, fatigue)
- Short-term memory changes
- Depression
What is the risk of estrogen in hormone-replacement therapy?
May increase the risk of endometrial and breast cancer
Why may estrogen therapy increase the risk of certain cancers?
Estrogen is a powerful mitogen (growth-promoting effects)
What may be used instead of estrogen in hormone-replacement therapy?
- Estradiol is converted to estrone in target cells, promoted by progesterone
- Estrone has a lower affinity to estrogen receptors, which may diminish cancer risks
What is the rate of bone loss without hormone-replacement therapy?
1 to 2% per year
What are causes of primary amenorrhea? (3)
- Genetic defects in gonadal maturation or estrogen synthesis
- Depletion of follicles
- Deficient hypothalamus or pituitary
What is secondary amenorrhea?
Failure to ovulate in a six-month period
What are causes of secondary amenorrhea? (5)
- Excessive androgen production
- Pituitary disease
- Disturbance of the cyclical release of GnRH
- Psychiatric disturbances
- Nutrition (bulimia, anorexia nervosa)
What are causes of failure of ovulation (i.e. menstrual cycle without ovulation)?
- Lack of positive feedback of estrogens
- Lack of pulsatility of GnRH release
- Lack of ovulation leads to irregular length of period
The detection of ovulation is based on what?
Progesterone surge
What occurs to basal body temperature during ovulation?
Rise of about 0.5oC
What occurs to the endometrium and plasma hormone concentrations during ovulation?
- Increase in endometrial mucosa secretion
- Increase in plasma progesterone or easier excretion of metabolites of progesterone
What is the function of clomiphene?
- Blockage of estrogen receptors in the tonic centre of the hypothalamus
- Prevents negative feedback by estrogens, and therefore increases LH and FSH
What may be injected to induce ovulation?
- LH, FSH, hCG
- Pulsatile injection of GnRH
What is the success rate for one ovum from in vitro fertilization?
10 to 12%
How are multiple ova obtained for in vitro fertilization?
Superovulation using gonadotrophin
What has a large effect on female infertility? Why?
Age due to age-dependent loss of follicles and increased rates of spontaneous abortion
Define fecundability. What is it for normal couples?
- Probability of achieving pregnancy within one menstrual cycle
- 25%
Why do the rates of spontaneous abortion increase with age?
The aging follicle has an increased rate of meiotic dysfunction due to chromosomal abnormalities
What are the three main causes of sub-optimal fertility?
1) Ovulatory defects (25%)
2) Pelvic disorders (30%)
3) Male factors (40 to 50%)
Give examples of pelvic disorders.
- Endometriosis
- Oviduct/uterine damage
What is endometriosis?
Presence of endometrial glands and stroma outside the uterus
What is the mechanism of action of in vitro fertilization?
1) Blockage of ovarian function to re-synchronize the ovary
2) Artificially inducing the growth of many follicles in the ovary by using LH, FSH and hCG
3) Super-ovulating the ovary and collecting eggs
4) Fertilize eggs in a dish, allowing the embryo to develop, which may be re-implanted in the woman
What prompts the pre-ovulatory center to release a surge of LH?
The largest follicle produces more and more estrogen (positive feedback on the surge center)
