13) Female Reproductive Endocrinology Flashcards
1
Q
What occurs in terms of germ cell development to form oocytes?
A
- Mitosis of oogonia
- Meiosis I to form oocytes
2
Q
What phase of meiosis do oocytes remain in until ovulation?
A
Prophase I
3
Q
Oocytes are surrounded by what to form a primary follicle?
A
Single granulosa cell layer
4
Q
How does male and female germ cell development differ?
A
- 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
5
Q
How are oocytes lost during in-utero development?
A
- May not progress through meiotic prophase
- May not successfully be enclosed in a follicle
6
Q
How many oocytes are present at birth and puberty? How many ovulations occur in a lifetime?
A
- Birth: 1.5 million
- Puberty: 300 000
- 400 to 500 ovulations in a lifetime
7
Q
What occurs in terms of the oocytes until puberty?
A
Waves of follicular growth and atresia
8
Q
What layer do granulosa cells form? What is its function? When does it develop?
A
- Corona radiata
- Provides nutrition for the cell
- Develops during the 5th month of in-utero development
9
Q
What occurs to granulosa cells once ovulation occurs?
A
They are removed
10
Q
Why is a larger follicle cell mass desirable?
A
To allow the fingers of the oviduct to pick up the cell with ease
11
Q
Where are thecal cells situated? Where are granulosa cells situated?
A
- Thecal cells are on the outside of the basement membrane
- Granulosa cells are on the inside of the basement membrane
12
Q
What is the corpus luteum responsible for if fertilization occurs?
A
The production of progesterone
13
Q
What occurs to the corpus luteum if fertilization fails?
A
Luteolysis
14
Q
Which gonadotrophin do thecal cells respond to? What is the response?
A
- LH
- Formation of testosterone
15
Q
Which gonadotrophin do granulosa cells respond to? What is the response?
A
- FSH
- Formation of estradiol from the testosterone produced in the thecal cells
16
Q
The antrum of a follicle is high in _________.
A
estradiol (E2)
17
Q
The estradiol produced by granulosa cells may affect which tissues?
A
- Brain (libido and sexual behaviour)
- Reproductive tract
18
Q
What is the importance of the high estradiol within the antral follicle?
A
Estrogen is a powerful mitogen
19
Q
_______ cells provide androgens to _______ cells.
A
thecal
granulosa
20
Q
_______ cells produce the circulating estrogens that inhibit the secretion of GnRH, LH, and FSH.
A
Thecal cells
21
Q
Inhibin from __________ cells inhibits FSH secretion.
A
granulosa
22
Q
LH regulates the ________ cells, whereas __________ cells are regulated by both LH and FSH.
A
thecal
granulosa
23
Q
When does estrogen and progesterone exert a positive feedback on the hypothalamus and anterior pituitary?
A
Days 12 to 14
24
Q
What produces inhibin A?
A
Dominant follicle and corpus luteum
25
What produces inhibin B?
Small follicles
26
When is inhibin A produced? When is inhibin B produced?
- Inhibin A: luteal phase
| - Inhibin B: follicular phase
27
What is the inhibin receptor?
- There is no specific receptor for inhibin
| - Inhibin acts by inhibiting activin
28
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)
29
What is recruitment?
- Small antral follicles are recruited
| - Entry into gonadotrophin sensitive pool
30
What is selection?
- Follicles are selected from previously small follicles
- Ovulatory follicles emerge
- They either undergo atresia or develop further
31
What is dominance?
Selected follicles will ovulate
32
What are the levels of FSH, LH, inhibin, and estradiol during recruitment?
- High FSH
- Low LH
- No inhibin
- Low estradiol
33
What are the levels of FSH, LH, inhibin, and estradiol during selection?
- Low FSH
- Moderate LH
- Low inhibin
- Medium estradiol
34
What are the levels of FSH, LH, inhibin, and estradiol during dominance?
- Low FSH
- High LH
- High inhibin
- High estradiol
35
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
36
At which phase is FSH at its lowest point? Why?
- Selection
| - The production of inhibin and estradiol inhibit FSH secretion
37
Estradiol exerts a positve feedback on the ______ center.
surge
38
The _____ center is ONLY associated with ovulation, while the ______ center is associated with other reproductive functions.
surge
| tonic
39
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
40
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
41
Which tissue layer contains the oocyte prior to ovulation?
Theca externa
42
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
43
How does the pre-ovulatory surge affect PGF2a?
Increase
44
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)
45
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
46
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
47
When does meiosis I occur in the oocyte? When does meiosis II occur?
- Meiosis I: ovulation
| - Meiosis II: fertilization
48
What three factors allow for the onset of ovulation?
- Elevated blood flow
- Breakdown of connective tissue
- Ovarian contractions
49
What do theca interna and granulosa cells become after ovulation?
Form the corpus luteum
50
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
51
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
52
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
53
What is the effect of progesterone produced by the corpus luteum on the mammary gland?
Positive feedback that promotes alveolar development
54
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"
55
Describe the mechanism by which the luteolytic pathway is activated.
Oxytocin produced by the ovary binds to receptor and activates the synthesis of PGF2a
56
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
57
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)
58
How do progesterone and estradiol concentrations vary during luteolysis?
Decrease dramatically
59
When may hCG be detected?
6 to 12 days after fertilization
60
hCG has the same alpha chain as which hormones?
- FSH
- LH
- TSH
61
What is the function of hCG?
Stimulates the corpus luteum to maintain steroids until feto-placental unit takes over
62
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
63
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
64
How do the levels of estrogen and progesterone vary as pregnancy progresses?
Increase as pregnancy progresses
65
The follicular phase is characterized by effects of which hormone?
Estrogen
66
The luteal phase is characterized by effects of which hormone?
Progesterone
67
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
68
In which structure does the fertilization of the ovum occur?
Oviduct
69
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
70
What allows for the movement of the ovum along the oviduct to the uterus?
Ciliated cells
71
What does the fertilized ovum derive energy from prior the implantation in the uterine endometrium?
Oviductal and uterine secretions
72
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
73
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
74
What is the function of trophoblasts?
Accomplishes implantation and develops into fetal portions of the placenta
75
What is the function of embryoblasts?
Cells that are destined to become the fetus
76
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
77
How do oral contraceptives affect estrogen and progesterone concentrations?
- Maintenance of high levels of progesterone (and estrogen, if combined)
- Maintaining an artificial corpus luteum
78
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
79
How does the IUD function?
- Blocks the sperm from reaching the oviduct
| - Slow release of synthetic progesterone (suppress ovulation)
80
How long does a progesterone injection last?
3 months
81
Is combined (estrogen and progesterone) or progesterone therapy alone more effective in terms of birth control?
Progesterone only is slightly less effective
82
How long does a progesterone implant last?
5 years
83
What does the Plan B pill utilize?
Synthetic progesterone
84
When should the Plan B pill be utilized?
Up until 72 hours after unplanned intercourse or suspected contraceptive failure
85
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
86
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
87
What pharmaceutical products induce abortion?
- Anti-progesterones
| - E.g. RU486
88
What is the mechanism of action of the progesterone antagonist, RU486?
The receptor complex binds, but gene(s) are not activated
89
What is the mechanism of action of the progesterone antagonist, ONA?
The receptor complex does not bind
90
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
91
Which chromosome does the placenta of a daughter always express?
The maternal X-chromosome
92
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)
93
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
94
After implantation, the blastocyst develops into a _________, and secretes ____.
trophoblast
| hCG
95
How does hCG affect LH and FSH? Why?
- hCG maintains steroid production by the corpus luteum
| - Suppresses LH and FSH
96
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
97
What happens to the DHEA produced by the fetal adrenal gland?
Converted to various estrogens by the placenta
98
How do estriol, estrone, and estrogen compare in terms of potency?
Estriol (E3) is a weaker estrogen than estrone (E1) and estrogen
99
Which particular estrogen increases during pregnancy?
Estriol (around 1000X the maximum pre-pregnancy values)
100
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)
101
How does the output of progesterone and estrogen by the feto-placental unit vary throughout pregnancy?
Continuously increases
102
What contributes to the progesterone in maternal circulation during pregnancy?
Synthesis by the placenta (week 9)
103
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
104
Which estrogens does DHEA produce?
- Estrone (E1)
| - Estradiol (E2)
105
Which estrogen does 16-hydroxy-DHEAS produce? When?
Estriol (E3) at week 12
106
When do changes in the breast occur in terms of puberty?
Two years before the end of puberty
107
What does estrogen stimulate in terms of breast development?
- Duct formation
| - Accumulation of fat
108
The effect of estrogen on the breast (increases/decreases) during pregnancy.
increases
109
Which hormones induce enzymes necessary for milk production during pregnancy? (3)
- Glucocorticoids
- Prolactin
- Placental lactogen
110
What inhibits milk production during pregnancy?
The high concentrations of estrogen and progesterone
111
How does milk production occur after parturition?
- Estrogen and progesterone levels fall
| - Prolactin stays high
112
What prevents ovulation during nursing?
High prolactin prevents normal cycling of GnRH
113
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
114
How does pregnancy affect the cardiovascular system?
- Increase in heart rate
| - Increase in cardiac output
115
How does pregnancy affect the respiratory system?
Increase in tidal volume
116
How does pregnancy affect the gastrointestinal system?
- Increased gastric emptying time
| - Decreased sphincter tone
117
How does pregnancy affect the renal system?
Increase in renal flow and GFR
118
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
119
What does estrogen stimulate during parturition due to an increase in cortisol? (2)
- Increased secretion by the uterus (lubrication)
| - Increased myometrial contractions
120
What does PGF2a stimulate during parturition due to an increase in cortisol? (2)
- Luteolysis
| - Myometrial contractions
121
What does relaxin stimulate during parturition due to an increase in cortisol?
Pelvic ligament stretching
122
What are the effects of myometrial contractions during parturition?
- Increased pressure
- Increased cervical stimulation
- Increased oxytocin
123
What injuries are more painful than parturition?
- Amputation of a digit
| - Causalgia (burning pain after partial injury of a nerve)
124
When do maternal steroids return to normal levels following parturition?
Within 1 to 3 days
125
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
126
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)
127
When is there a sudden drop in the number of follicles in women?
37 years old
128
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
129
How do steroid hormones vary after menopause? How do pituitary hormones vary after menopause?
- Decrease in steroid hormones
| - Increase in FSH and LH
130
Why is there an increase in GnRH, LH, and FSH after menopause?
Because there is reduced negative feedback
131
What are menopausal symptoms that may be treated with estrogen?
- Vasomotor
- Urogenital atrophy
- Osteoporosis
- Psychosocial (insomnia, fatigue)
- Short-term memory changes
- Depression
132
What is the risk of estrogen in hormone-replacement therapy?
May increase the risk of endometrial and breast cancer
133
Why may estrogen therapy increase the risk of certain cancers?
Estrogen is a powerful mitogen (growth-promoting effects)
134
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
135
What is the rate of bone loss without hormone-replacement therapy?
1 to 2% per year
136
What are causes of primary amenorrhea? (3)
- Genetic defects in gonadal maturation or estrogen synthesis
- Depletion of follicles
- Deficient hypothalamus or pituitary
137
What is secondary amenorrhea?
Failure to ovulate in a six-month period
138
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)
139
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
140
The detection of ovulation is based on what?
Progesterone surge
141
What occurs to basal body temperature during ovulation?
Rise of about 0.5oC
142
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
143
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
144
What may be injected to induce ovulation?
- LH, FSH, hCG
| - Pulsatile injection of GnRH
145
What is the success rate for one ovum from in vitro fertilization?
10 to 12%
146
How are multiple ova obtained for in vitro fertilization?
Superovulation using gonadotrophin
147
What has a large effect on female infertility? Why?
Age due to age-dependent loss of follicles and increased rates of spontaneous abortion
148
Define fecundability. What is it for normal couples?
- Probability of achieving pregnancy within one menstrual cycle
- 25%
149
Why do the rates of spontaneous abortion increase with age?
The aging follicle has an increased rate of meiotic dysfunction due to chromosomal abnormalities
150
What are the three main causes of sub-optimal fertility?
1) Ovulatory defects (25%)
2) Pelvic disorders (30%)
3) Male factors (40 to 50%)
151
Give examples of pelvic disorders.
- Endometriosis
| - Oviduct/uterine damage
152
What is endometriosis?
Presence of endometrial glands and stroma outside the uterus
153
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
154
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)
