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Male System Anatomy Part 18-Basics of Cancer Cytogenetic-Lecture Handout, Exercises of Cancer Cytogenetics

Sree Chitra Tirunal Institute of Medical Sciences and TechnologyCancer Cytogenetics

This lecture handout was designed and distributed by Prof. Akhilesh Kulkarni at Sree Chitra Thirunal Institute of Medical Sciences and Technology. This is part of Cancer Cytogenetic course. It includes: Staph, Coliforms, Diphtheriods, intoxication, Intramyometrial, Necrosis, Prostaglandisn, Menstrual, Contractility, Adrenomedullin

Typology: Exercises

2011/2012

Uploaded on 08/01/2012

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IN SUMMARY
HST 071
TERMINATION OF PREGNANCY
Complications of Saline AB
• Fever and infection – 2 to 16%
– Pyrogens ?
– Staph, coliforms, diphtheroids. Strep
• Hemorrhage (w or w/o DIC) – 4 %
• Coagulopathy
• Siezures
– Headaches, thirst, water intoxica tion
• Peritoneal spillage – peritonitis
• Bladder injection
• Intramyometrial inj ection – necrosis
• Rh isoimmunization (transplacen tal hemorrhage)
Surgical Techniques
• ≤ 14 Weeks:
– Suction Curettage
– Medical Abortion (≤ 56 days LMP)
• 14-24 Weeks and Beyond:
– Dilatation and Evacuation (D+ E)
– Intact D+E (“D+ X”) {evacuation/extraction}
– Labor Induction Methods (Prostaglandins)
– Amnioinfusion (HS, Urea, Pros taglandins)
Cervical Dilatation
• Mechanical:
o Done at Time of D+E
o Convenient for Pa tient
o May be Uncomfortable
o Increased Risk of Perforation (Compared with Osmotic Dilators)
• Osmotic Dilators (e .g. Laminaria)
o Increased Time, Inconvenience
o Less Pain, Decreases Perforation Risk
• Examples:
o Laminaria japonicum, L. digitatu m
o Dilapan
o Lamicel
Laminaria
• Hydroscopic seaweeds
– Laminaria digitata
– Laminaria japonicum
• Gamma radiation
– Does not kill spores
• Various sizes
– Strings
– Collar
171
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TERMINATION OF PREGNANCY

Complications of Saline AB

  • Fever and infection – 2 to 16%
    • Pyrogens?
    • Staph, coliforms, diphtheroids. Strep
  • Hemorrhage (w or w/o DIC) – 4%
  • Coagulopathy
  • Siezures
    • Headaches, thirst, water intoxication
  • Peritoneal spillage – peritonitis
  • Bladder injection
  • Intramyometrial injection – necrosis
  • Rh isoimmunization (transplacental hemorrhage) Surgical Techniques

• ≤ 14 Weeks:

  • Suction Curettage
  • Medical Abortion ( ≤ 56 days LMP)

• 14 - 24 Weeks and Beyond:

  • Dilatation and Evacuation (D+E)
  • Intact D+E (“D+X”) {evacuation/extraction}
  • Labor Induction Methods (Prostaglandins)
  • Amnioinfusion (HS, Urea, Prostaglandins) Cervical Dilatation

• Mechanical:

o Done at Time of D+E o Convenient for Patient o May be Uncomfortable o Increased Risk of Perforation (Compared with Osmotic Dilators)

• Osmotic Dilators (e.g. Laminaria)

o Increased Time, Inconvenience o Less Pain, Decreases Perforation Risk

• Examples:

o Laminaria japonicum, L. digitatum o Dilapan o Lamicel Laminaria

• Hydroscopic seaweeds

  • Laminaria digitata
  • Laminaria japonicum

• Gamma radiation

  • Does not kill spores

• Various sizes

  • Strings
  • Collar 171
  • Blunt tip
  • Several apertures
  • Reuseable (ethylene oxide, glutaraldehyde)

TERMINATION OF PREGNANCY

Laminaria

• Inserted 3-6 hours prior to surgery

• May be up to one day

• Past internal os

• Usually results in at least 8 mm dilation

• Direct dehydrating effect on cervix

• Provoke release of prostaglandins

• 12 fold decrease in cervical lacerations

Suction Curettage

• Office, Clinic or Hospital Setting

• Local (Paracervical Block) or IV Sedation

• General Anaesthesia Increases Risk

• Prophylactic Doxycycline Decreases Endometriitis Risk

• Rigid or Osmotic Dilators Used

• “No-Touch” Technique

Dilatation and Evacuation

• Avoid Mechanical Dilatation if Feasible

• Requires Additional Experience and Training

• Safer than Amnioinfusion in Most Cases when Performed by Experienced Operator

• Less Emotionally Traumatic for Most Patients (Compared With Labor Induction)

Complications

• Bleeding

• Infection

• Retained POC

• “Missed Abortion”

• Perforation – low risk, high risk variants

• Hematometra (“postabortal,” or “re-do” syndrome)

• Undiagnosed Ectopic Pregnancy

Menstrual Regulation

  • Aspiration up to 50 days LMP
    • Menstrual extraction
    • Menstrual aspiration
    • Menstrual induction
    • Minisuction
  • Extremely safe
    • 4 - 6 mm Karman cannula
  • Foot or hand pumps
  • Syringes 172

TERMINATION OF PREGNANCY

Initiation of Parturition

  • Fetus is in control in most viviparous animals
  • Sheep and cow fetus triggers labor
  • Human placenta lacks glucocorticoid-inducible enzyme 17(alpha)-hydroxylase-17,20-lyase
  • Regardless final pathway for labor ends in the uterus
  • Characterized by the development of regular phasic uterine contractions Initiation of Parturition
  • Myometrial contractions mediated through the ATP-dependent binding of myosin to actin
  • Myometrial cells are sparsely innervated
  • become even less so during pregnancy.
  • Regulation of the contractile mechanism largely humoral
  • Parturition cascade at term
  • Removes the mechanisms maintaining uterine quiescence
  • Recruits factors promoting uterine activity
  • Multiple positive-feedback loops Initiation of Parturition
  • Series of changes within the myometrium, decidua, and cervix
  • Occurs over a period of days to weeks
  • Synthesis and release of prostaglandins within the uterus
  • Formation of myometrial gap junctions
  • Activation of myometrial oxytocin receptors
  • Endocrine, paracrine, and autocrine factors
  • switch in the pattern of myometrial activity from irregular contractures to regular contractions Physiologic Actions of Drugs Inducing Abortion
  • Implantation of a fertilized ovum (embryo)
  • Complex interactions with the endometrium.
  • Embryo becomes attached to the endometrial epithelium
  • Invades the endometrial stroma on day 6 to 10 after ovulation.
  • Depends on progesterone which
  • Modifies the transcription of many genes involved implantation process
  • Inhibits myometrial contractions
  • Drugs used to terminate pregnancy
  • Inhibiting synthesis of progesterone,
  • Inducing myometrial contractions,
  • Antagonizing the action of progesterone
  • Inhibiting the development of the trophoblast. 174

TERMINATION OF PREGNANCY

Role of Progesterone

  • Progesterone binds to its receptor
  • Complex forms a dimer and binds to a segment of the promoter region of different target genes
  • This genomic effect leads to changes in the structure of epithelial-cell membranes
  • Synthesis of implantation proteins
  • Progesterone decreases uterine contraction, probably by a genomic effect.
  • In contrast, during labor, oxytocin and prostaglandins induce uterine contraction.
  • Prostaglandins and oxytocin bind to their respective receptors
    • Increased phospholipase C activity
    • Increased intracellular inositol triphosphate (IP(3))
    • Increased calcium
  • The released calcium interacts with myosin light-chain kinase (MLCK) on the contractile filaments to cause uterine contraction.
  • Progesterone also exhibits nongenomic action by binding to oxytocin receptor and inhibiting the action of oxytocin
  • During a normal pregnancy blastocyst attaches to the receptive endometrium, or decidua, on day 6 or 7 after ovulation.
  • The trophoblast then traverses adjacent cells and invades the endometrial stroma.
  • The agents used to terminate pregnancy are
    • Methotrexate - which inhibits trophoblast division
    • Prostaglandins - which increase muscle contraction
    • Epostane - decreases progesterone synthesis
  • Mifepristone - progesterone antagonist
    • blocks the binding of progesterone to its receptor
    • amplifies the action of prostaglandins on the myometrium
    • induces cervical softening Oral Agents
  • Ergot
  • Quinine
  • Strychnine
  • Whiskey
  • Turpentine
  • Phosphorus
  • Castor oil
  • Rosemary, nutmeg, aloe, cloves, thyme
  • Spanish fly
  • Arsenic, copper, lead, mercury
  • Folate antagonists Prostaglandins
  • Mifepristone
  • Misoprostol
  • Gemeprost 175

TERMINATION OF PREGNANCY

inflammatory drugs. Prostaglandin Side Effects

• Dose related

• Fever

• Chills

• Gastrointestinal

• Lactation

• Bronchospasm

• Pre-treatment with Lomotil/Compazine

Efficacy of Prostaglandins

  • Oral doses of misoprostol ranging from 400 to 3200 micrograms induce abortion in only 4 to 11 percent of women with pregnancies of 56 days' duration or less.
  • Bioavailability is greater when the drug is administered vaginally and higher success rates have been reported with vaginal administration.
  • Results with doses ranging from 800 to 2400 micrograms vary considerably
    • Rates of complete abortion of 22, 47, 61, and 94 percent have been reported.
    • Differences not related to the dose of misoprostol or the duration of gestation Side Effects of Prostaglandins

• High incidence of side effects

  • Pain, dizziness, nausea, vomiting, diarrhea, chills, and rashes.
  • Fifty-three percent of women given 5 mg of gemeprost required opiate analgesia, as compared with 16 percent given 3 mg
  • Women receiving more than 3 mg of gemeprost frequently had to remain in the hospital overnight

• Misoprostol failures

  • Scalp or skull defects, cranial-nerve palsies, and limb defects such as talipes equinovarus

• The increase in uterine pressure related to uterine contractions or vascular spasm may be

the cause MIFEPRISTONE

  • 19 - norsteroid
  • AFFINITY
    • progesterone receptor - strong
    • glucocorticoid receptors - strong
    • androgen receptors – less
  • Stimulates synthesis of PG by decidua
  • Available
    • France
    • United kingdom
    • Sweden
    • China
  • 1980 compound synthesized at Roussel-Uclaf (hence RU - 486)
  • Became available in France soon thereafter
  • Teutch (1975) studied how small chemical alterations in steroid molecules affected ability to bind - Developed a method of synthesizing versions of steroids that did not exist in nature - Alain Belanger (post-doc) the produced the molecules
  • Initial effort was to produce a gluco-corticoid antagonist to aid wound healing 177

• Observed for 4 hours

• 2/3 abort in this time

TERMINATION OF PREGNANCY

  • Most potent was RU-38486 which was also found to block progesterone

• Teutsch

• Belanger – postdoctoral fellow

• Deraedt – progesterone binder as well

• Sakiz – corp. exec. Created formal project

• Barton – Nobel Laureate chemist

• Philibert – supvr. Of RU-486 project

• Hodgden – East Va med Sc. – TAB in monkey

• Bailieu & Hermann (Geneva) – TAB in humans

Timetable

  • 1950 – Aminopterin (folate antagonist used to produce medically indicated abortions
  • 1972 – PGE2 and PGF2 α induced abortion (intolerable side effects)
  • 1975 – Selective prostaglandin analogs (still had side effects)
  • 1980 – More stable analogs (gemeprost {PGE1 methyl ester}, sulprostone {16- phenoxyl- tetranor-PGE2})
  • 1982 – Etienne-Emile Baulieu investigated glucocorticoid blockers and discovered RU- 486 (mifepristone)
  • 1985 – Addition of prostaglandin aided in expulsion
  • 1988 – Licensed in France
  • 1993 - Methotrexate Rationale for Use of Mifepristone
  • Progesterone needed to sustain early pregnancy
  • W/o progesterone uterus expels pregnancy
  • Through prostaglandin mediated mechanism
  • Epostane (3 β - hydroxysteroid dehydrogenase inhibitor) prevents synthesis of progesterone {dosing every 6 hours for many days)
  • Mifepristone binds the receptor with equal affinity as progesterone without activation
  • Alters endometrium by affecting the capillary endothelium of the decidua (trophoblast separates and bleeding ensues)
  • Also affects the tissues of the cervix MIFEPRISTONE

• Most effective in early pregnancy

• 7 weeks or less LMP have 95% rate

• 9 weeks have 80%rate

• No good studies above 9 weeks

• Similar to miscarriage

• Use narcotics rather than NSAIDS

• 1% need curretage

• .1% need transfusion

MIFEPRISTONE

• Three visits

– 600 mg mifepristone (5% expel)

– 400 ug cytotec orally 48 hours later

– Return in 2 weeks for checkup

– Dose not yet established (200 to 600 ug)

• 600 mg orally

178

TERMINATION OF PREGNANCY

180