• oogenesis
• synthesize and secrete sex steroid hormones
  • estrogen
  • progesterone
  • androgen

• from wk 8-9 to 6 months of age, the oogonia enter meiosis and become primary oocytes

1. primary stage- primary oocyte grows
   • granulosa cell proliferation nurtures oocyte, produces hormones
   • primordial follicle develops into primary follicle
2. after puberty, second stage (over 70-85 days)
   1. granulosa cells and theca cells continue to grow
   2. only occurs during reproductive period
3. stage three (5-7 days after menses)
   • one follicle becomes dominant over others
     • nondominant follicles regress
     • dominant follical grows to 20 mm diameter
   • day 15-28: ovulation occurs
     • dominat follicle ruptures
     • releases oocyte into peritoneal cavity

• first meotic division is completed
• secodary oocyte enters fallopians tube and begins second division
  • completed in oviduct only if fertilization oiccurs
• residual elements of ruptured follicle form corpus luteum
  • primarily granulosa cells, theca cells
  • synthesized and secretes steroid hormones needed for implantation and zygote maintenance
  • Fate of hormone levels
    • fertilization- continues hormone secretion until placenta take over
    • no fertilization- regresses until get corpus albicans

1. in theca cell (stimulated by LH)
   1. cholesterol converted to androstenedione and testosterone via cAMP stimulated cholesterol desmolase
2. androstenedione and tesosterone go to the granulosa cell (stimulated by FSH)
   1. via cAMP stimulated enzyme, converted to estrogen and estradiole

• synthesize and secrete progesterone and testosterone
• express 17 beta hydroxysteroid dehydrogenase

• express aromatase
• convert testosterone to 17 beta estradiol via aromatase (stimulated by FSH)

• intermitent via a pulse generator
• produced in arcuate nucleus of hypothalamus
• decapeptide encoded by gene on chromosome 8

• follicular phase- pulses more frequent and smaller amplitude (estrogen increases frequency)
• luteal phases- pulses larger but less frequent (progesterone decrease frequency)

1. GnRH released to act on gonadotrops in anterior pituitar
2. GnRH receptor is a G protein coupled receptor
   1. stimulates phospholipase activity
   2. increase inracellular calcium
3. leads to synthesis and release of LH and FSH in a pulsatile manner

• mechanism of action
  • G protein coupled receptor that activates adenylate cyclase to increase cAMP
• function
  • act at theca cells
  • stimulate synthesis of androstenedione and testosterone
  • rupture of dominant follicle
  • induce expression of FSH receptors on granulosa
• gene at chromosome 2p

• function
  • stimulate growth of developing follicles
  • induce expression of LH receptors on theca and granulosa cells
  • stimulate aromatase activity, leading to increase estradiol production
• mechanism of action
  • G coupled (increase cAMP
• at 2q chromosome

• E2 rises durin follicular phase due to LH stimulation of theca cells and FSH stimulation of granulosa cells
• right before the LH surge, there is a spike in estradiol production, which will cause LH to shoot up

• negative feedback
  • FSH, LH stimulate estradiol secretion
  • at lower estradiol levels, this will inhibit secretion of FSH, LH

• midcycle: positive feedback
  • estradiol rise sharply (when we get above 200 pg/mL and hold it there over 50 hours)
  • enhances secretion of LH/FSH- LH surge

• negative feedback
  • progesterone is the major hormone secreted and is inhibitory
  • estrogen levels ar moderate
  • progesterone negatively feedback to suppress FSH and LH

• maturation and mainteneance of uterus, fallopian tubes, cervix, vagina
• puberty, secondary sex characteristics
• proliferation of granulosa cells
• negative and positive feedback regulation of FSH and LH
• lowers urterin threshold to contractile stimuli
• maintenance of preganancy
• block action of PRL on breast (inhibit milk production)

• maintenance of secretory activity of uterus during luteal phase
• reduces estrogen proliferative effects on uterus
• important for maintenance of pregnancy
• negative feedback effects on FSH, LH
• maintenance of preganancy
• raises uterine threshold to conractile stimul to pregnancy
• stimulate transient breast epithelial proliferation followed by growth arrest

• increase, maintenance of bone mass
• decrease osteoclast effects
• minor increase in osteoblast activity

Without estrogen, leads to osteoporosis

• increase body temperature
  • midcyle increase one degree (persist through cycle)
  • alters CNS temperature regulatory center

• alter serum lipids
  • elevate HDL
  • slight increase in TAGs
  • decrease LDLs
• vasodilation
• decrease fasting blood glucose and insulin

• changes in lipid levels
• increase basal insulin levels
• vasodiliation (greater than estrogen)

1. estrogen diffuse into cell
2. bound by estrogen receptor, lead to confirmational change
3. binds to piece of DNA
4. stimulates transcription, make mRNA, which makes protein
5. change cellular physiology

• phosphorylation can lead to:
  • ligand independent activity
  • synergism with agonist/antagonists
  • phosphorylation of coactivator proteins

• alpha- mainly in femal reproductive tract, but also in lung, brain, vasculature
• beta

Highest expression in prostate, ovaries.

44% identical in AA sequene

• regulatory (18% homology btw alpha and beta)
• DNA binding (96% homology btw alpha and beta)
• hinge region
• hormone binding (56% homology btw alpha and beta)
  • within is a TAF2 domain
    • in order to have full receptor activity, its needed (active after confirmation change when binding to estrogen)

• alpha knocked out in the ERKO mice
  • absent breast development at puberty
  • normal lifespan
  • infertile males, females
  • normal genitourinary development but no adult response
  • anovulatory
• beta knocked out in BERKO
  • normal breast glands and function
  • normal lifespan
  • fertile males, subfertile females
  • normal genitourinary development and adult response
  • oligovulatory

1. when estrogen binds to estrogen R, it causes dimerization that changes confirmation
2. can now bind to estrogen response element
3. upon binding, complrex recruits coactivatory molecules
   1. SRC1 (steroid receptor coactivator)
   2. CBP (cAMP response element binding protein)
4. these proteins recruit other proteins including HAT's (histone acetylases)
   1. causes nucleosomes to urravel, so DNA is open up
   2. transcription machinery can now come in

• allows shape change and dimerization
• allows coactivators to bind and attract other proteins such as transcription machinery

1. bind to same pocket causes shape change
2. shape is different and allows for attraction of corepressors and blocks attraction of coactivators

Inhibition of transcription

Produce responses in genes that lack an estrogen response element

• AP-1
  • prevents or stimulates interaction with other transcription factors regulatory sequences
    • can be isoform specific
    • how estrogen regulates other genes without ERE
• other signals activated
  • ERK, MAPK

1. corepressors/coactivators
2. another TF

What happens depends on the cell you are in.

• A (mediates majority of inhibitory effects)
  • slightly smaller than B
• B (mediates majority of stimulatory effects)

On the same gene (splice variants), with the same ligand binding domain from the same nuclear receptor family

estrogen receptors

glucocorticoids receptors

androgen receptors

• public and axillary hair growth
• acne

1. after the first year of life, pulse generator is quiscent
2. right before puberty, inhibition decreases
   • increase amplitude, frequency of pulse
   • further increases in amplitude and frequency occur throughout puberty until adult pattern established

• first sign of puberty is breast budding followed by pubic and axillary hair, and menses
  • many of first cycles are anovulatory
  • breast development is estrogen dependent
    • tissue enlarge
    • areola darkenrapid increase in stature occurs after puberty

• several years prior, anovulatory cycles (skipping periods or lenght between periods greater) become more common
  • number of functioning follicles decrease
  • decrease estrogen secretion and eventually ceases
  • obese women have fewer symptoms than nonobese because estrogen produced in adipose

• thinning of vaginal epithelium
• decrease vaginal secretion
• accelerated bone loss
• decrease breast mass
• vascular instability, hot flashes
  • hot flashes happen at the end of pregnancy (hormone levels just drop)
• emotional lability

1. fertilization must take place within 24 hours of ovulation in distal part of the oviduct (ampullae)
   1. second polar body extruded
   2. ovum begins to divide
2. blastocyst arrives in uterus four days after fertilization
3. implantation occurs

1. blastocyst float in uterus for days
2. implant 5 days after fertilization
   1. must have low E/P ratio for implantation to occur (due to progesterone output by CL at highest)
3. trophoblast (outer rim cells of blastocyts) invade endometrium and forms attachment with maternal membranes
   • fetal part of placenta
4. P4 stimulate endometrium to differentiate into decidual cells that envelop fetus
5. trophoblastic cells proliferate to form syncytiotrophoblasts (allow blastocyt to penetrate deep into endometrium)
6. trophoblast begin to secrete hCG 8 days after ovulation

1. function- signal CL that fertilization has occured
2. mechanism of action
   1. bind to LH receptor
   2. stimulate corpus luteum to continue synthesis of progesterone and estrogen to maintain endometrium
      • suppress development of next batch of follicles

• oxygen
• water, electrolytes
• carbs, lipids, AA's, vitamins
• some hormones
• Ab's
• some drugs
• viruses (most)

• carbon dioxide
• water, urea
• waste products
• hormones

• HbF has higher affinity for oxygen
  • at PO2 of 30-35, we get 80-90% saturation
• mom will breath off the CO2 we give her (respiratory rate increase)

• hCG rescue CL
• hCG levels maximal at gestational week 9 and then decline
• most organ development
• time where most sensitive to chemically induced birth defect
  • greatest chance if exposed from 31 days after last menstrual period to 71 days after last menstrual period

• alcohol
• ACE inhibitors
• anti-seizure medications

• placenta now the main producer of sex steroids
• progesterone produced from maternally derived cholesterol
• estrogen require mother, placenta, and fetus

• physical- distension leads to increase contractility
• E/P ratio increases
  • increase uterine sensitivity to contractile stimuli
• PG's of E and F serios
  • increases uterine contractility (Braxton Hicks contractions)
• OT
  • stimulate uterine contraction, but levels do not increase near termp
  • receptors for OT upregulated

• cyclic nonapeptide
• secreted by nerve endings that terminate on post. pit.
• synthesized by paravent. cells as part of larger molecule (some produced in supraoptic nucleus)
• differs by two AA's with vasopresin
• secreted in pulsatile mann er

• stretching of cervix (stimulates frequency and force of contraction)
• suckling (stimulate milk ejection)

via G coupled proteins

1. uterine contractions move head toward cervix, progressive widening and thinning of cervix
2. fetus forced through cervix and delivered through vagina
3. placenta separates from uterine tissues is delivered
   1. uterine contractions constrict uterine blood vessels and limit post partum bleeding

1. during pregnanc, E and P stimulate growth and development of breast but block effect of PRL on breast
2. estrogen stimulates PRL secretion and they increase over course of pregnacy
3. after partuition, E and P fall and their inhibitory effects PRL are removed
4. lactation maintained by suckling
   1. stimulate OT and PRL secretion

• regulated via inhibition of hypothalamus
  • dopamine receptors on lactotrophs inhibit PRL secretion
    • dopamine release inhibited by suckling, so increase PRL
• secretory stimulation via TRH
• PRL inhibits GnRH (lactation)