reproduction - F repro pt 2 Flashcards
Primary amenorrhea – what is it, and what are common causes
Absence of menses in phenotypic female by age 17
Causes:
Disorders of sexual differentiation such as turner syndrome (XO), cmplete androgen resistance (XY), and hormonal disorders in ovaries, , adrenals, thyroid, HPA axis
Secondary amenorrhea - what is it and what are common causes (as well as others)
Cessation of menses for >6 months
Common causes: Pregnancy, lactation, and menopause
Others: Prolactinoma, panhypopituitarism
Oligomennorrhea – Common causes , and some other causes
Infrequent periods, cycle lengths >35 days
Changes due to functional abnormalities in CNS mechanisms that regulate GnRH release including stress and illness
Changes in body fat composition, intense exercise, extreme weight loss , anorexia nervosa - no consistent changes in plasma gonadotropins or ovarian steroids
What is clomiphene
First used to treat oligomenorrhea; blocks estrogen receptors in brain; makes it useful as a fertility drug because induces HPG axis from lack of negative feedback; induces ovulation in PCOS
Dysmenorrhea
Painful menses related to uterine contractions ; main involve pelvic pain radiating to back, thighs, nausea, vomiting, and diarrhea; Caused by PG synthesis which is promoted by E2 followed by P4.
What do Prostaglandins released in menses cause?
Uterine contractions; may be severe enough to cause ischemia and pain
Causes dysmenorrhea
(single most common cause of female work/school absenteeism, treated with oral contraceptives and PG synthesis inhibitors)
Premenstrual syndrome and premenstrual dysphoric disorder
- when does it occur in ovarian cycle?
- what is the result?
- how is it treated
Occurs in late luteal phase
Both physical and behavioral symptoms that interfere with normal life; very normal (this is PMS, so irritability, bloating, etc)
Treated with SSRi’s and oral contraceptives to suppress ovulation
Hirsutism
- What is it?
- Common causes
Inappropriate heavy hair growth in androgen sensitive areas
Excessive androgen production by adrenals (ex. adrenal hyperplasia or Cushing Syndrome) or intake of exogenous androgens and idiopathic increases in sensitivity to androgens
Common symptom of PCOS
Virilization
Includes hirsutism and more pronounced evidence of androgen stimulation such as clitoral hypertrophy, deepening voice, temporal balding, male pattern skeletal muscle development (excess androgen production is a big cause)
PCOS
- What causes it?
- What is the result of this? Including: Weight management, and what’s going on with the generation of those ovarian cysts?
Root cause - insulin resistance and obesity (caused by and causes OF PCOS)
High insulin –> high androgen production –> causes infertility
in addition:Increase in conversion of estrogens due to excess androgens, which leads to excessed weight gain
Follicle development is imaired; ovulation is not completed and follicles degenerate into cysts. Overall, ovary doubles in size.
Symptoms of PCOS
Sleep apnea, menstrual irregularity, acne, besity, decreased HDL and increased TGs, hirsutism
Treatments for PCOS
Weight loss, cessation of smoking, metformin (insulin release) - metformin alone is often sufficient to restore fertility.
Clomiphene which helps induce ovulation is also helpful in PCOS cases
menopause
Age related cessation of ovulation (happens between 48-52)
How do you know you’re entering menopause? What are the hormone sensitivity problems?
Onset frequency of anovulatory bleeding increases and cycles become irregular with gradual diminution of menstrual flow. Sensitivity of follicles to FSH ad LH declines; follicles disappear, ovarian generation of estrogens drop and maintain of lower generations of steroids depend on peripheral conversion of androgen precursors secreted by adrenal glands.
After menopause, what is the dominant estrogen?
Estrone
Loss of negative feedback from estradiol and inhibin causes what?
3-4x increase in FSH + LH with FSH being greater than LH due to slower GnRH pulsitility; this ratio remains in absence of cyclicity of the ovarian cycle.
Symptoms and consequences of menopause (5)
- Osteoporosis (increase in bone resorption due to less OPG activation from less estradiol and less bone formation)
- CV disease risk goes up - increase in cholesterol, LDL, and decrease in LDL receptors (increase in risk of atherosclerosis
- Thinning of vaginal epithelium and decreased secretions
- decreased breast mass
- vascular flushing (hot flashes) due to CNS mediated changes in GnRH
HRT and post menopausal women - set up of experiment, results?
Two paradigms: Women given conjugated equine estrogen alone OR horse estrogen and progestins (if uterus present)
Found that there was a greater risk of CV, venous thromboembolism, breast cancer, fracture, colorectal cancer, etc. However, later studies have called this into question; particularly becaue many of the women were in later stages of menopause, and people who were in perimenopause had very beneficial outcomes, wehreas those who had it later had negative outcomes
Timing hypothesis of HRT
There is a window of opportunity - you must give HRT to menopausal women at the right time
What are peak fertility ages
18-25
Where does fertilization occur
in fallopian tube – within 24h after ovulation (12-16 days post previous menses)
how is gestational age calculated
from first day of last menses
What is fetal age
2 weeks less than gestational age
When is the best time to get preggo
24h post ovulation for ovum; 48-72h post coitus
After embryo implatns into endometrium, what special organ is formed?
placenta
What is the function of the placenta
endocrine gland; takes over steroid and protein hormone synthesis to support developing embryo
Symptoms of pregnancy follow what?
placenta formation
Symptoms of pregnancy
Breast tenderness, fatigue, nausea, absence of menstruation, softening of uterus, sustained elevation of body temperature
what is the final stage of gestation?
Parturition
What influences Parturition?
fetal and maternal factors
Gamete transport – how fast do sperm reach ampula and how long do they live
Reach ampulla within 5 mins, retained 24-48 h
50-100 reach this point
What are factors that assist in sperm transport? (5)
1- vaginal secretions become more alkaline
2- uterine contractions and cervical contractions propel sperm forward
3- prostaglandin in seminal plasma induces muscle contractility
4- Seminal “plug” coagulates upon ejaculation
5- vaginal mucus becomes less viscous
How many oocytes are released from ovary into peritoneal cavity
One
At ovulation, what is released into the surrounding peritoneal cavity?
oocyte and the cumulus oophorus
how are sperm and ovum mixed
churning motion of the ampulla wall
Where does fertilization usually occur?
In the ampulla - this is where the first stages of embryonic development occur as well. This is the devleopment of the blastocyst
What is sperm capacitation?
Functional properties of sperm acquired in female tract that allow for penetration of zona pellucid of egg; poorly understood, thought to include removal or modification of protein coat covering sperm and may involve vagina, uterus, cervix. It makes sperm competent to undergo acrosomal reaction.
Acrosomal reaction (3)
- Sperm binds to ZP3 protein on zona pellucida (glycoprotein)
- Triggers increased calcium in sperm cell - leads to exocytosis of hydrolytic enzymes
- Sperm and oocyte membranes fuse - acrosome reacted sperm bind to ZP2 proteins
Cortical reaction
Spermatozoon penetration then triggers calcium increase in oocyte, resulting in fusion of cortical granules with plasma membrane. This releases enzymes that harden glycoproteins of zona pellucida This is including exocytosis of sperm internal contents and exocytosis of oocyte’s internal vesicles. The same increase in calcium that triggers the cortical reaction also triggers the end of meiosis II – then the second polar body is released, leaving oocyte with haploid, unduplicated chromosomes. Fusion with male pronucleus leads to zygote formation.
What happens as meiosis completes
De-condensation of sperm DNA. Oocyte is released from metaphase II and finishes Meiosis II, second polar body is extruded and the oocyte has haploid, unduplicated chromosomes
Transport of blastocyst to uterus - how long does the transfer take, and what does the timing and arrival depend on?
Timing is 3 days, depends on balance effects of progesterone and estrogen
Estrogen - causes constriction of isthmus barring passage of embryo to uterus
Progesterone levels later incleas, promoting myometrium relaxation and transport of blastocyst to uterus
What does embryo adhesion require
maternal and fetal factors
Fetal factors that support embryo adhesion
Syncytiotrophooblasts secrete adhesive surface proteins such as cadherins and integrins; these factors attach bridging molecules secreted by maternal uterine glands
maternal factors that influence embryo adhesion
Uterine glands secrete estrogen dependent substances like osteopontin, which ind to surface proteins secreted by blastocyst; stromal cells of uterus form decidua and begin secreting nutrients for fetus that will develop; stromal structure eventually becomes barrier and acts as endocrine organ
What is the decidua
thick layer of modified mucus membrane
what is hatching of the embryo
Dissolution of zona pellucida by trophoblast cells
what is blastocyst implantation
Trophoblast differentiates into cytotrophoblasts and cyncytioprotoblasts
what are cytotrophoblasts doing
Feeder for continually dividing cells (initially)
What do syncytiotrophoblasts do?
3 functions Adhesion, invasion, and endocrine functions
How far does embryo burrow
completely into endometrium
What determines invasion?
balance between decidual cells (defense) and trophoblast migration (offense)
Matrix metalloproteinases from trophoblasts vs inhibitors in the decidual cells; IGF2 is secreted from trophoblasts vs IGF binding proteins from decidua. The balance prevents invasive trophoblasts from penetrating too deeply
4 steps of embryo attachment and invasion into endometrium
A. Trophoblast differentiates into cytotrophoblasts and syncytiotrophoblast layers
B. Lacunae filled with maternal blood are formed as syncytiotrophoblast layer increases in size and penetrates deeper
C- implanatation is nearly complete; cytotrophoblast cells begin to form primary villi, which are covered by layer of syncytiotrophoblast cells
D- Implantation is complete; embryo fully invades endometrium, extraembryonic mesoderm forms inner layer of villi (secondary villi) - mesoderm will then give rise to tertiary villi which forms core of villus containing umbilical blood vessels
What are lacunae
Fluid filled spaces in syncytium that make contact with maternal blood vessels
What forms chorionic villus?
cytotrophoblasts proliferating and invading syncytiotrophoblasts
What is the mature villus
fetal tissue protruding into maternal blood brush border of syncytiotrophoblast faces maternal blood
What happens to the spiral arteris in placental formation
increase in diameter and they get thinner ; which increases placental perfusion. Failure to develop vasculature results in placental ischemia
Preeclampsia - hallmark symptoms and pathophysiology
Symptoms: Hypertension, proteinurea, and edema
Pathophysiology: Placenta has ischemia leads to oxidative stress and endothelial cell changes; damaged endothelial cells lead to increase in vasoconstriction and decrease in vasodilators –> worsens placental ischemia –> endothelial barrier between basement membrane and platelets is breached which leads to thrombosis, clotting, capillary leaks, edema, and proteinurea
5 roles of the fully developed follicle
Maintain and nurture resident oocyte, mature oocyte and releaase it at appropriate time, prepare vagina and fallopian tubes for fertilization, prepare uterine lining for accepting and implanting zygote, maintaining hormone environment for fetus until placenta can take over
what are theca cells, what do they produce, and what receptors do they have?
main hormone precursor cells with LH receptors ; generate androgens (androstenedione) and progestins
What are granulosa cells, what hormones do they produce, and what receptors do they have?
Estrogens, progestins, inhibins, they have LH and FSH receptors
They provide support to help develop oocyte
3 phases of ovarian cycle
Follicular
ovulatory
luteal
Follicular phase
Development of the dominant follicle takes about 10-14 days
Ovulatory phase
rupture of follicle and release of oocyte into peritoneal space; 1-3 days
Luteinizing phase
Formation of corpus luteum (14 days or less, variable)
3 phases of the endometrial cycle
Menstrual
Proliferative
Secratory
When is the menstrual phase
Early follicular phase
when is the proliferative phase
follicular phase
when is the secretory phase
luteinizing phase
When are germ cells of a female produced
first 20-24 weeks of gestation (by mitosis)
By 6 months after the baby is bon, what stage are the oocytes at and how long will they be like this
arrested in meiosis 1 diplotene stage where they will remain until puberty (at the earliest)
What are primordial follicles? What are they composed of? Are there theca cells?
Primordial follicles exist in utero; they are composed of small granulosa cells and no theca cells in a single row. They are arrested at diplotene stage of prophase I.
What are primary follicles? What are they composed of? What hormone stimulation do they need to develop? Can this happens in utero?
Yes can happen in utero. This is the next stage of follicular development, where there is a slightly bigger granulosa cell – require FSH to develop– the granulosa cells are now cuboidal
What part of the gonadal ridge does the female reproductive tract arise from?
The cortex (male arises from medulla)
Secondary follicle - what is it, what happens to the stromal cells, what happens to the oocyte?
Oocyte gets more enlarged and granulosa cells proliferate. Stromal cells become theca cells.
Early antral follicle/ tertiary follicle - what do the granulosa cells do, and what do they secrete closest to oocyte and furthest from oocyte
Granulosa cells will begin secreting antral fluid or (closest to oocyte) mucoglycoproteins that will form the zona pellucida . The oocyte will continue to enlarge.
Mural cells
Granulosa cells furthest from oocyte that have lots of LH receptors and are metabolically active
Cumulus cells
Granulosa cells next to the oocyte that form a light covering and will be shed at time of ovulation
Antral cells
Granulosa cells which face the antrum and form luteal cells after ovulation
At the point of choosing the dominant follicle, what stage of development is the oocyte arrested at
Diplotene stage (will remain there until LH surge)
At the end of the ENTIRE ovarian cycle (at end of luteinization phase) is FSH or LH higher, and why is this important?
FSH is higher and this will help recruit follicles to enter next follicular phase
What hormone is produced by recruited follicles, and what is the significance of this?
Inhibin B:
This will increase steroidogenesis in theca cells directly, activate pituitary to generate more LH to activate theca cells to augment steroidogenesis, and provide negative feedback on FSH (decreased FSH ensures only follicle most sensitive to FSH is going to survive)
Inhibin A is produced by what, and what does it do?
corpus luteum; augments progesterone in luteal phase
What is the 2 compartment theory of estradiol synthesis
Theca cells have LH receptors so they synthesize androgens; and then the granulosa cells have LH and FSH receptors. So the FSH cells stimulate LH receptor expression, which is required for response to LH surge. FSH also increases aromatase expression, and this converts the androgens to estrogen.
What are the 4 steps of follicle maturation
- Cumulus cell expansion - forms corona radiata and cumulus oophorus
- Detachment of cumulus-oocyte complex - free floats in antrum
- Follicle forms bulge against ovarian wall (stigma)
- The osmotic pressure in antral fluid increases as polysaccharides begin to depolymerize and granulosa cells of cumulus oophorus loosen in preparation for ovulation
2 steps of oocyte maturation – what is the result
oocyte completes meoisis 1
arrests at metaphase in meiosis –> results in secondary oocyte and polar body
4 steps of ovulation
rupture of ovarian wall
2- extrusion of cumulus-oocyte complex
3. increased vascularization
4- differentiation of mural granulosa cells into large luteal cells, and theca cells into small luteal cells
What organ determines timing of LH surge and what hormone does it require
Ovary; sustained exposure to estradiol
What effect does estrogen have on progesterone
increases sensitivity to progesterone by increasing progesterone receptors in preparation for luteal phase
what happens to corpus luteum during luteal phase
becomes more dominant in role; makes lots of progesterone and estrogen (mostly progesterone)
What is the effect of progesterone and estrogen during luteal phase, ad what does this mean for FSH, LH, and GnRH secretion?
Negative feedback from P4 and E2 – less FSH, LH, and GnRH
What does loss of LH mean for corpus luteum?
begins to die unless rescued by equivalent hormone secreted by embryo, hCG
What hormone is in charge of proliferative phase, what is result?
Increased level of estrogen, due to the growing follicles, which stimulates proliferation of endometrium and expression of progesterone receptors to prepare for secretory phase. And you also have increased vascularization.
What hormone is in charge of secretory phase, what are uterine glands doing?
Uterine glands begin secreting carb rich mucus, endometrium becomes engorged and stroma becomes edematous. Vascularization continues to increase, stromal cells undergo predecidualization. High progesterone levels antagonize proliferative effects of estrogen, so proliferation slows
What happens in menstrual phase?
Low estrogen and progesterone due to corpus luteum dying; this reduced blood flow leads to ischemia in endometrium. Tissue becomes necrotic and proteolytic enzymes increase to digest this; endometrium sloughs off.
What does estrogen do to growth of cohort follicles?
Inhibitory
E1 estrogen
E2 estrogen
E3 estrogen
Estrone (mainly after menopause, lower affinity for estrogen receptors
Estradiol (main one in reproductive years)
Estriol (main one in pregnancy)
Which ER, alpha or beta, is associated with reproductive effects
alpha; beta is nonreproductive effects
What does progesterone do?
Prepares Endometrium for implantation, inhibits myometrial contractions (so you don’t spontaneously miscarry), stimulates mammary gland development (preparation for being a cow), antagonizes actions of estrogen (important consideration for HRT)
