Placental Gonadotropins

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Chapter 5

• Placental Gonadotropins
• Prostaglandins

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Placental Hormones

• -Pregnant Mare Serum Gonadotropin (PMSG)
• -Also called equine Chorionic Gonadotropin
  (eCG)
• -human Chorionic gonadotropin (hCG)
• -Placental Lactogen (PL)

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• PMSG
• Discovered when blood from pregnant mare produced
  sexual maturity in immature rats
• Chemistry
• Glycoprotein with ? and ? subunits
• Similar to LH and FSH
• Higher content of sialic acid-
• How does this affect the hormone?
• i.e. Half- life is many hours(24)
• One injection can have an effect at target tissue
  for more than a week
• Molecular wt. 40,000

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PMSG

• -Secreted by endometrial cups in the equine
  uterus
• -Believed to be primarily of fetal origin
• -Endometrial cups are formed about day 40 of
  pregnancy and persist until day 85
• -Found in blood between day 40-160
• What is the difference between serum and
  plasma?

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Function of PMSG

• -Has both FSH and LH-like activity with higher
  degree of FSH-like activity.
• - Secretion of PMSG stimulates development of
  follicles on the ovary due to FSH effect
• - Some of these follicles may ovulate
• - Most follicles become luteinized without
  ovulating due to low LH potency
• i.e. accessory CL? P4 production
• -Isolate from blood of pregnant mares- not found
  in urine possibly due to large molecular size ?
  cant clear glomerular capsules of the kidney

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Application

• -Used to induce superovulation in domestic
  animals
• -Superovulation and embryo transfer of cattle,
  sheep, pigs not the mare
• -Stimulates testosterone production
• i.e., ram which had low sperm count
• -Stimulation of puberty in gilts at 180 days of
  age

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Superovulation

• Ewes- 600- 1000 IU of PMSG SQ on D 12-13
• Cow- FSH 2x daily for 4 or 5 days
• 5 mg/injection
• 25-35 mg PGF2? IM
• or
• 5 mg 4-3-2-2- x2 injections daily
• or
• Single doses of PMSG 2000-2500 IU
• Must check potency
• Best response is when treatments are started on
  day 9-11. If started earlier than day 18 must
  give PGF2? starting on day 15 to coincide with
  natural estrus. Multiple artificial inseminations
  should be done to insure maximum number of
  fertilized ova.

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hCG

• -Also a glycoprotein with ? and ? subunits
• -molecular wt. 40,000 daltons
• -Has both FSH and LH activity with
  predominately LH action
• -Produced by chorionic villi of the placenta in
  primates
• -Detected as early as day 8 of pregnancy
• -Implantation occurs around day 7
• -It converts the CL of the menstrual cycle in
  the human to the CL of pregnancy

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Application

• -Detected in both blood and urine
• -Urine detection allowed for development of human
  pregnancy tests
• -Treatment of cystic ovaries in cows
• -5,000 to 10,000 IU of hCG
• -Follicle either ovulates and forms a CL or more
  often just luteinizes
• -Causes production of progesterone and CL is
  usually functional for 20 days and will then
  regress normally
• -Cycle 21 days after injection

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• Sows 750-1500 IU on Day 15 of the cycle-- then
• 500 IU HCG at onset of estrus
• Pregnancy restores responsiveness to
  superovulatory hormones

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Prostaglandins
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• 1935
• Von Euler coined prostaglandin
• Allen and Corner coined progesterone

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Prostaglandins

• Not localized in any particular tissue
• Most PGs act locally at site of production or by
  a cell-to-cell interaction
• Can also be transported in the blood
• All prostaglandins are 20-carbons non-saturated
  hydroxy fatty acid with a cyclopentane ring.
  Arachidonic acid, an essential fatty acid is the
  precursor for prostaglandins.

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Prostaglandins

• Unsaturated hydroxy acids with five- membered
  ring in a 20-carbon skeleton
• A F Series
• E
• Occur in nearly all mammalian tissues
• - Larnyx - Brain
• - Spinal cord - nerve tissue
• - seminal plasma
• - skeletal muscle

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• - Kidney
• - adrenals
• - fat -ovaries
• - thyroid -stomach
• - uterus
• First detected in ram seminal plasma
• Concentration
• a. Usually 1 ug/g. of wet tissue
• b. Exception- seminal plasma 100 pg/ml

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Involved in

• Control of blood pressure
• Lipolysis
• Intestinal peristalysis
• Gastric secretion
• Blood clotting
• Uterine contractions
• CL regression
• Ovulation

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• Prostaglandins appear to act locally rather than
  as a classical circulating hormone.
• Biological activity
• 1. Both alteration of smooth muscle
  contractility and modulation of hormonal activity
  were detected following Prostaglandin
  administration
• 2. Adenyl cyclase AMP system appears to be
  involved in action of PG as modulators

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• PGF2? was detected in maternal venous blood
  obtained either at the time of spontaneous
  abortion or at full term labor and the
  concentration increased with the progression of
  labor

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• Endometrial tissues incubated in vitro
  synthesized prostaglandins from natural
  precursors.
• This presence of PGF2? in amniotic fluid and
  blood during labor plus their known effect on
  stimulation of contraction of isolated myometrial
  tissue led to hypothesis that prostaglandins
  played a major physiological role in parturition

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• Dexamethasone-induced parturitions resulted in
  significantly elevated levels of PGF2? in
  maternal cotyledons and myometrium. Progesterone
  will suppress uterine activity but will not
  inhibit PGF2? increases in cotyledons

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Prostaglandins have been shown to have both
luteolytic and oxytocic properties

• For those species in which a functional CL is not
  essential for pregnancy maintenance, the primary
  actions may be oxytocic, i.e., disruption of the
  fetal maternal placental unit.
• For those requiring a CL, PG may contribute to
  reducing serum progesterone levels through CL
  regression.
• Also has been suggested that prostaglandins in
  seminal plasma may facilitate sperm transport in
  the female

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Mechanisms of Parturition

• Two processes Uterine contractions
• Cervical dilation
• PG- determines the time of parturition
• Raising E2 declining P4- stimulate PGF2?
  synthesis
• -induces strong uterine contractions
• -causes cervical dilation
• Fetal influence- raise cortisol-converts P4 to E2
  
• Increased E2 leads to increased PGF2?
  secretion

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Prostaglandins role in reproduction

• 1. Involved in ovulation in cow and ewe
• -If given indomethacin (inhibits PG synthesis),
  ovulation is blocked
• -LH release is not affected, so the action and
  synthesis of PG is at the level of ovary
• -May manifest LH activity
• 2. Prostaglandins E2 stimulates contraction of
  the uterus, dilates large blood vessels

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• 3. PGF2? stimulates contractions of uterus,
• aids in sperm transport,
• causes constriction of blood vessels
• and has luteolytic properties

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Prostaglandins role in reproduction

• Certain conditions must be met for CL regression
• Functional CL
• Susceptibility of CL to prostaglandins ( PG
  receptors present)

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Luteal regression by PGF2?

• Hypothesis PGF2? may induce hypoxia, which
  results in luteolysis.
• Remember
• -PGF2? is involved in constriction of blood
  vessels
• -The CL receives the greatest amount of blood
  flow/g of tissue compared to all other tissues

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Conditions for luteal regression

• A functional CL must be present
• Susceptibility of CL to PGs
• Cow and ewe- PGF2? will not cause regression or
  prevent formation of CL during its first five
  days of life
• Sow- PGF2? will not cause regression until day 12
  of the estrous cycle
• Must consider these species differences when
  incorporating estrous cycle synchronization
  treatment regimes using PGF2?

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• Uterus- regulates the function of the CL
• -cycle vs. pregnant
• -In the ewe it appears that PGF2? is the uterine
  luteolysin
• -Increase in estrogen increases myometrial growth
  of uterus which stimulates PGF2? synthesis and
  release

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Estrous Synchronization

• 1. Progesterone injections
• Reduced conception rates at synchronized estrus
• 2. 1968 estrogens are luteolytic in cow
• 3. Development of polymer implants with single
  injection of norgestomet and Estradiol Valerate
  (SMB)
• 4. Abbot Labs- Progesterone Releasing
  Intravaginal Device (PRID) not marketed

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Estrous Synchronization

• PGF2? - lyses mature CL
• -Lutalyse -Bovilene
• -Estrumate

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Certain conditions must be met

• Functional CL
• Susceptibility of CL to prostaglandins
• Prostaglandins may be either oxytocic or
  luteolytic

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• Major limitation to cycle control inconsistent
  onset of puberty in heifers and postpartum estrus
  in cows
• Most important endocrine event
• a. Establishment of episodic pulsatile
  luteinizing hormone (LH) secretion
• Recent research indicates endogenous opioid
  peptides may be responsible for anestrus in
  suckling beef cows
• Opioids such as beta-endorphin and methionine
  enkephalin decrease LH
• Opioids apparently inhibit GnRH secretion

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Alternating Reproductive Process

• Synchronization of estrus Cattle
• SMB
• PGF2?
• MGA PGF2?
• Pessary -sheep Flugesterone acetate - causes
  sperm damage-lessened by using intrauterine
  insemination
• Altrenogest (Trade name Regumate) - swine

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Potential Outcomes

• Improve herd quality
• (use of AI)
• Result in calves being born earlier in calving
  season
• (older, heavier and uniform
• at weaning)
• Increase reproductive performance of heifer or
  cow
• (calve earlier in calving season,
  breed back earlier)

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Products Used to Synchronize Estrus in Cattle

• Three Primary Luteolysins
• Prostaglandins (each contain PGF or synthetic
  PGF)
• Trade Names
• Lutalyse injectable
• Estrumate injectable
• IN SYNC injectable

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Three Primary Progestogens

• Progestins
• Norgestomet (Syncro-Mate B) implant
• Melengestrol Acetate (MGA) oral feed additive
• Controlled Internal Drug Release (CIDR)
  vaginal insert

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Three Primary GTH Releasers

• GnRH products
• Cystorelin
• Factrel
• Fertagyl

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Syncronization Product Doses

• Lutalyse 5ml, IM
• Estrumate 2ml, IM
• IN SYNC 5ml, IM
• MGA 0.5 mg/hd/day, orally
• Cystorelin 2ml, IM
• Factrel 2ml, IM
• Fertagyl 2ml, IM

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Costs of Synchronization

• Will depend on many factors
• Labor
• Facilities
• Products
• AI supplies
• Effectiveness of protocol used
• Cost of clean up bull

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Product Costs

• Lutalyse 2.50/dose
• MGA 240/ton
• GnRH 3.50/dose

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Success of Synchronization

• Must have
• 1. Good Nutrition program
• 2. Healthy animals
• 3. Females exhibiting regular estrous cycles
• 4. Willingness to learn new products
• 5. Adequate facilities
• 6. Accurate record keeping

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Natural Service vs. AI

• Natural Service
• Bull purchase 2,000
• Salvage value 600
• Bull maintenance 1,095
• Purchased interest 600
• Risk(10) 200
• Total Cost 3,200
• Cost/natural calf 43.93

• Artificial Insemination
• Semen Purchased 15
• AI Service 5.00
• Syncronization 7.00
• Total Cost 27.00
• Cost/AI calf 27.00