Physiology Block 3 Week 13 Female Reproductive Endocrine Flashcards
How is genetic sex determined?
Genetic sex is determined at conception
The lack of hormonal signals lead to female phenotype–required to develop male phenotype
What gene is leads to development of male phenotype?
H-Y antigen–encoded by SRY (sex-determining region of Y-chromosome)
In absence of testis, what is not developed?
In absence of testis, ovaries form
There is a lack of androgen production
- no testosterone or its conversion to DHT in target tissues
- no Mullerian inhibiting factor (induces regression of mullerian ducts)
Without these 2 hormones:
Wollfian ducts regress and Mullerian ducts develop into female reproductive tract
Follicle Growth in the ovary
Pre-antral follicle has ovum
Follicle developed inside Granulosa and Theca cells
Once developed ovulates egg and can be fertilized
What’s left after ovulation is the corupus luteum
- -produces primarily progesterone
- -if egg not fertilized and does not implant, corpus luteum dies
Atresia
At 6 months gestation, will have 7 million oognoia (potential ova)
Oogonia start to degenerate which continues until menopause
At birth, about 600,000 oogonia remaining
Pattern of hormones and oogonia from:
- Gestation
- Birth
- Puberty
Middle of gestation (fetus):
A burst of FSH and LH
Human chorionic gonadotropin (hCG) wanes
–important for stimulating oogonia
Birth (2-6 months): Lose hCG Another burst of FSH and LH -Males: stimulates testes to produce androgen -Females: unknown
Before Menarche (puberty):
Pituitary secretion of FSH and LH
–induces ovarian function to produce estrogen
–stimulates growth spurt (Growth Hormone)
Female Steroidogenesis
3 Estrogens:
- Estrone (E1)
- Estradiol (E2): estrogen of non-pregnant women
- Estriol (E3): estrogen of pregnant women
AROMATASE (A) necessary to convert androgen to estrogen
Androstenedione (A)–> E1
- -> E2
- -> E3 (liver)
Androstenedione–>Testosterone (A)–> E2
- -> E1
- -> E3 (liver)
Steroid Distribution in Plasma and Binding Proteins
Most steroids bound to a carrying protein–very little is free
Cortisol Binding Globulin (CBG)–cortisol only, no estrogen, some progesterone (cortisol precursor)
Sex-Hormone Binding Globulin (SHBG)–binds sex hormones (mainly androgens) testosterone and estrogen
Albumin–estrogen will bind albumin more than SHBG
What initiates puberty in females?
Hypothalamic GnRH and Pituitary gonadotropins (FSH and LH) are released in pulsatile manner
Body fat and intake of calories may stimulate puberty in girls
–Gymnasts, anorexic (refusal to eat), and bulemic girls fail to have menstrual cycle (amenorrhea)
Leptin (from adipose tissue) signals hypothalamus to increase GnRH pulses
Kisspeptin
Estrogen has negative feedback on hypothalamus and pituitary
–when high, prevents release of GnRH
Leptin (from adipose tissue) activates neurons that activate kisspeptin, which actives GnRH neurons to pulse
- -leads to increased FSH and LH release
- -leads to ovaries producing more estrogen
Female Puberty
Leptin activates kisspeptin, which activates pulsatile release of GnRH, which activates pituitary to make FSH (and a little later LH)
- FSH wakes up ovary follicles
- follicles increase estrogen production
Simultaneous development of breast/pubic hair and growth spurt
- -peak growth velocity is earlier in girls than boys
- -estrogen induces closure of growth plates in long bones
Last thing to develop is 28 day menstrual cycle
–If not having regular menstrual cycles by 16, need to be checked
Menstrual Cycle: Follicular Phase
- Death of corpus luteum due to:
- -no pregnancy
- -hCG not released by the trophoblast into maternal blood
Results in:
- -decreased progesterone (necessary for secretory phase of uterine cycle)
- -decreased estrogen
- Loss of progesterone and estrogen negative feedback
Results in:
–FSH (primarily) and LH
- FSH induces maturation of next group of follicles
- -a dominant follicle develops (from 6-12) and autonomously releases estrogen
Results in:
- -estrogen increase decreases FSH and LH via negative feedback
- -dominant follicle can survive loss of FSH and LH –atresia of non-dominant follicles
- When estrogen peaks induces hypothalamic-pituitary switch to positive feedback
- -estrogen stimulates a SURGE in LH (and to a lesser degree FSH)
- -LH surge required for ovulation induction
Menstrual Cycle: Luteal Phase
- LH surge stimulates ovulation
- -formation of corpus luteum (what’s left)
- -dominant follicle stops making estrogen, terminating LH surge - Corpus luteum produces progesterone
- -inhibits FSH and LH secretion - Corpus luteum dies if:
- -no pregnancy
- -no release of hCG from trophoblast into maternal blood
Generation of Positive Feedback-Induced LH surge
Early Follicular Phase:
- dominant follicle produces estrogen that acts LOCALLY to stimulate induction of FSH receptors on granulosa cells
- allows survival of FSH decrease
Mid-Follicular Phase:
Non-dominant follices have died due to FSH decrease
Local estrogen positive feedback induces:
-more FSH receptors
-LH receptors
-proliferation (division) of granulosa cells
Late Follicular Phase:
- follicle loaded with granulosa cells (proliferation)
- estrogen peaks in blood (due to increased granulosa cells), inducing positive feedback stimulation of LH and FSH leading to LH surge
- LH surge stimulates follicle to expel egg
All the cells left behind form corpus luteum, which produces progesterone
Interaction of Follicular Theca and Granulosa Cells
Production of estrogens
Theca cell:
- makes LH receptors
- no aromatase
Granulosa Cell:
- makes FSH receptors
- expresses LH receptors mid-cycle
- aromatase present
- LH binds receptor on theca cell
- Androgens produced
- Androgens diffuse into granulosa cell
- FSH acts on granulosa cell and stimulates aromatase activity
- Conversion of androgen to estrogen
When follicle becomes more dominant, granulosa cell expresses LH receptor
- LH binds receptor on granulosa cell
- Production of progesterone (from cholesterol)
- Progesterone shuttled into Theca cells
- In Theca cells, progesterone converted to androgen
- Androgen diffuses into granulosa cell for conversion into estrogen under FSH stimulation
Need both Theca and Granulosa Cells to produce estrogen
Effect of Estrogen on Reproductive Tract
Estrogen predominates during follicular (proliferative growth) phase
Oviduct
- Lining: increased cilia formation and activity (want to be ready to transport egg if fertilized)
- Muscular Wall: increased contractility
Uterus
- Endometrium: increased proliferation (growth)
- Myometrium: increased growth and contractility
- Cervical Glands: watery secretion (allows sperm to get in)
Vagina:
- increased epithelial proliferation
- increased glycogen deposition
Effect of Progesterone on Reproductive Tract
Progesterone predominates during luteal (secretory–slow things down) phase
Oviduct
- Lining: increased secretion (help get to uterus)
- Muscular wall: decreased contractility
Uterus
- Endometrium: increased differentiation and secretion (ready for implantation)
- Myometrium: decreased contractility (want uterus quiet rather than pushed out)
- Cervical Glands: Dense/viscous secretion (to prevent germs getting in or egg leaving)
Vagina
- increased epithelia differentiation
- decreased epithelial proliferation
Myometrial (Uterine) Cycle
Estrogen dominates proliferative (follicular) phase (11 days), so thickness of endometrium grows dramatically
Progesterone from corpus luteum (12 days) dominates secretory (luteal) phase and stimulates secretions so if fertilized egg comes along, endometrium is ready for implantation
If no implantation occurs or hCG present to rescue corpus luteum, it dies (end of luteal phase)
–progesterone and estrogen plummet
Menstrual phase (5 days)
- -uterine spiral artery supplying blood to endometrium vasoconstricts
- -endometrium dies and sloughed into menstrual bleed
Which of the following is an example of positive feedback?
A. Effect of progesterone on LH and FSH in luteal phase
B. Effect of estrogen on LH and FSH in the late follicular phase
C. Effect of estrogen on LH and FSH in early follicular phase
D. Effect of decreasing progesterone in the late luteal phase
B. Effect of estrogen on LH and FSH in the late follicular phase
How is corpus luteum rescued by hCG?
Follicular phase, estrogen predominates
Positive feedback of estrogen results in LH surge
–ovulation in 24 hours
–fertilization in 24 hours
Fertilization usually in oviduct (fallopian tube)
–begins development as works way to uterus
At uterus, now a blastocyts (Day 5)
- -implanted into myometrium (Day 7)
- -makes blood connection to maternal circulation
Placenta/trophoblast begins making hCG
- -looks like LH, FSH, TH due to alpha subunit (beta unit = activity)
- -goes into maternal circulation and rescues corpus luteum
Corpus luteum continues making estrogen and progesterone
–keeping FSH and LH low inhibits next menstrual cycle
hCG
Stimulates estrogen and progesterone release from corpus luteum
–inhibits GnRH (hypothalamus) and Anterior pituitary gonadotropin secretion (FSH and LH), which prevents next menstrual cycle during pregnancy
Stimulates continued growth of endometrium to nurture growing implanted embryo and fetus
Steroidogenesis in Trophoblast
Trophoblast implants into endometrium
- -takes up LDL (for cholesterol)
- -cholesterol converted to pregnenolone (mitochondria)
Pregnenolone converted to progesterone (SER) and secreted into maternal circulation
Also, pregnenolone passed to fetus
–taken up by fetal adrenal to make adrenal steroid end-products
Steroidogenesis in Plancenta
Placenta has lots of aromatase
Maternal adrenal testosterone converted to estradiol (E2) in trophoblast
Maternal adrenal DHEA converted to estrone (E1) in trophoblast
Fetal adrenal synthesizes DHEA (from trophoblastic prognenolone) and sulfates it in fetal zone
- -in fetal liver, DHEAS converted to 16-OH-DHEAS
- -converted to Estriol (E3)
Estriol used as a marker of fetal distress
- Fetal Adrenal function
- Fetal Livers function
Why is estriol used as a marker for fetal distress?
Assesses:
- Fetal Adrenal function
- Fetal Livers function
How do the concentrations change in pregnancy?
- Estrogen
- Progesterone
- hCG
hCG peaks in the first trimester
Placenta makes most of the estrogen and progesterone during 2nd and 3rd trimester (unregulated production)
–hCG wanes because corpus luteum no longer necessary
Estrogen and Progesterone increase as placenta gets bigger
Changes of Anterior Pituitary hormones during pregnancy:
- GH
- LH, FSH
- ACTH
- TSH
- PRL
GH–no change
LH and FSH–low during pregnancy bc estrogen and progesterone inhibit menstrural cycle
ACTH–no change
TSH–wobbles because maternal TH important in developing fetus (1st trimester):
- TBG increases
- reaches nadir (1st trimester) then plateaus
Prolactin–increases steadily during pregnancy bc mammary glands stimulated so tissue is there to produce milk after parturition
Changes of placental proteins during pregnancy:
- hCG
- hPL
- CRH
hCG–(homology with FSH and LH) increases, then declines
hPL–(homology with GH) increases steadily.
-thought to contribute to insulin-resistant state bc want maternal blood glucose to go up a little to feed baby
CRH–burst at end may contribute to onset of parturition
–stimulates ACTH
Changes of fetoplacental estrogen during pregnancy
All increase!
Estriol (E3) increases most
Estradiol (E2)
Estrone (E1)
Changes of fetoplacental androgens during pregnancy:
- Testosterone
- DHEA
- Androstenedione
Fetus and placenta can make androgens
Testosterone–increases
–most from maternal adrenal glands
DHEA–decreases
Androstenedione–small increase
Changes in thyroid hormones during pregnancy:
- Total T4
- fT4
- Total T3
- fT3
Estrogen stimulates production of thyroid binding globulin (TBG)
As estrogen increases, amount of TBG increases
Total T4 and T3 increase because there are more binding sites
–happens SLOWLY
–reaches a new baseline/steady state
Ex. Person who gets packed RBC has same PO2. RBC suck up O2, BUT lungs suck in a little more O2. The moles O2 taken in is small compared to O2 bound to Hb
Free TH never really changes
–conceptually TH goes down, but happens so slowly over months that will never be able to detect it
Changes in cardiovascular system during pregnancy:
- HR
- BP
- SV
- CO
- Peripheral venous distention
- TPR
BP = CO x TPR CO = HR x SV
Placenta needs more blood
–parallel resistance circulation lowers TPR
Ex. Less resistance if more doors open to escape room.
HR--inc CO--inc dramatically BP--dec (despite CO inc) TPR--dec SV--inc
Changes in pulmonary system during pregnancy:
- RR
- Tidal Vol
- Expiratory Reserve
- Vital capacity
- Respiratory minute vol
Placenta needs O2, so alveolar ventilation goes up–hypernea (inc in breath irrespective of metabolism)
RR--no change Tidal Vol--inc Expiratory Reserve--dec to increase lung efficiency--get more O2 exchange for same TV Vital capacity--no change Respiratory minute vol--inc
Changes in blood during pregnancy:
- Volume
- Hematocrit
- Fibrinogen
- Electrolytes
If going to pump more blood (CO), need to make more blood
Volume–inc
Hematocrit–dec (Red cell mass/ Plasma volume)–plasma volume change is greater than red cell mass
Fibrinogen–inc
Electrolytes–no change
Changes in gastrointestinal system during pregnancy:
- Sphincter tone
- Gastric emptying time
Sphincter tone–dec
Gastric emptying time–inc
Changes in renal system during pregnancy:
- Renal flow
- GFR
Lots of metabolic waste being produced by fetus–need to get rid of this
Renal flow–inc
GFR–inc
Changes in weight during pregnancy:
- uterine weight
- body weight
Uterus gets bigger to accommodate growing fetus
Parturition
Fetus gets so big that it out lives its space
Something happens in the fetus that turns on fetal adrenal gland
Aromatize androgens to estradiol
Stimulates uterus contractility and sensitivity to oxytocin leading to parturition
Theory for onset of strong labor contractions
- Baby’s head stretches cervix
- Cervical stretch excites fundic contraction
- Fundic contraction pushes baby down and stretch cervix some more
- Repeat
Oxytocin
As fetus head presses on cervix, afferent nerves carry impulses to hypothalamus such that oxytocin released from posterior pituitary
–oxytocin stimulates uterine contractions that inc cervical stretch (positive feedback)
After placenta delivery, estrogen and progesterone decrease
- -lots of milk produced, but not released due to progesterone
- -suckling stimulates oxytocin release and stimulating milk let down
Breast and Mammary Gland
Mammary gland:
- secretory lobules
- alveoli
- lactiferous duct
Myoepithelial cells synthesize milk
–oxytocin forces contraction and pushes milk into ductules
Rates of secretion after parturition:
- estrogens
- progesterone
- prolactin
At parturition, no longer have placenta hooked to maternal circulation
Estrogen and progesterone plummet
- -releases mammary glands from inhibition
- -when baby suckles, stimulates oxytocin AND prolactin to maintain milk synthesis
2 months post-partum, prolactin levels are not high, but are stimulated every time baby suckles
Prolactin inhibits FSH and LH release
–burst of prolactin prevents onset of new menstrual cycle for a period of time
Even though suckling, normal menstrual cycles can resume
Control of Prolactin release
Pregnancy or suckling reduces activity of dopoadrenergic nerves in hypothalamus
- -releases lactotroph from dopamine inhibition
- -lactotroph produces prolactin
Estrogen secretion throughout the sexual life of female human being
Estrogen low in first 10 years of life because GnRH pulses are not there
–FSH and LH are low
Calories, leptin, etc. stimulates GnRH pulses in hypothalamus (kisspeptin)
–FSH and LH pulses increase
Ovaries stimulated (FSH), which start making follicles and begin menstrual cycle
45-50–menopause due to ovarian failure
- -No more follicles left, can’t have a dominant follicle making estrogen
- -Pituitary is normal, and no longer receives negative feedback from estrogen
- –will have abrupt increase in gonadotropins from GnRH pulses
In men, gonadotropins increase a little
Mechanisms of Osteoporosis Due to Reproductive Events/Disorders
Osteoporosis–loss of bone mass
Loss of gonadal steroids removes the anti-resorptive (bone break down) effect, allowing loss of bone mineral
Females:
- oophrorectomy
- Turner’s syndrome
- ovarian failure
- hyperprolactinemia (prolactin secreting tumor)–inhibits pituitary gonadotropin secretion leading to hypogonadism
- Exercise associated amenorrhea
- menopause
Males:
- hypogonadism
- advanced age
Which of the following is usually decreased at the end of the 3rd trimester of pregnancy?
Maternal prolactin Maternal hematocrit Maternal TSH Maternal respiratory minute volume Maternal total T4
Maternal prolactin–inc
Maternal hematocrit–DEC–(Red cell mass /
Plasma volume)–more plasma volume than red cell mass
Maternal TSH–wobbles, nadir, then plateau
Maternal respiratory minute volume–inc
Maternal total T4–inc due to more TBG
