Endocrine and obstetrics

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Endocrine and obstetrics

• Tom Archer, MD, MBA
• UCSD Anesthesia

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Hormone

• From the Greek to stimulate or excite
• My version of the theme is SIGNALING.

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Short term effect of glucose uptake into muscle
Long term anabolic effects
http//casestudies.med.utah.edu/med1/diabetes2/ima
ges/web/Insulin_signalling_pathways.jpg
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Insulin is an ANABOLIC hormone

• Insulin affects gene transcription, promoting
  tissue growth and health.

Insulin is NOT just about blood glucose control!
Google images
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Insulin

• Anticoagulant
• Vasodilatory
• Anti-inflammatory
• Anabolic
• Insulin even reduces augmentation index!

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Are hormones building new machinery (e.g. tissue
growth)? (Slow)
http//www.eng.vt.edu/warelab/images/Klages20Mach
ine20Shop.jpg
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Or are hormones turning on pre-existing
machinery (e.g. glucose uptake into
muscle)? (Fast)
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Hormones

• Do they act slowly or quickly?
• Do they rapidly control pre-existing machinery
  such as contracting smooth muscle cells (e.g.
  angiotensin II), or
• Do they slowly make new structures, such as
  hypertrophied cardiac or vascular muscle (e.g.
  angiotensin II or aldosterone)?

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Hormones

• Can have multiple sites of action and
• Multiple time courses and mechanisms of action.

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Examples of hormones having multiple sites of
action

• Dobutamine inotrope AND improves
  microcirculation in septic shock.
• Insulin regulates uptake of glucose into muscle
  (at multiple sites) AND supports tissue growth
  and protein synthesis AND supports vasodilation
  AND
• Angiotensin II causes vasoconstriction AND causes
  vascular stiffening and cardiac hypertrophy.
• Stiff aorta causes increased pulse wave velocity
  and aortic pressure augmentation.
• ACE inhibitors reduce heart damage (CHF) and
  renal damage.
• AVP (ADH) causes vasoconstriction (V1) AND free
  water retention (V2).

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The sophisticated physician

• Will appreciate the multiple actions of hormones
  many that are still unknown!

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Complex action of hormones

• Short term, catecholamines and RAAS help the CV
  system to handle stress (fight or flight).
• Long term, they hurt CV system by causing
  remodeling (cardiac and vascular stiffness due
  to fibrosis and smooth muscle hypertrophy).

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Many current agents appear to block long term bad
effects of sympathetic and RAAS systems on heart
and kidney

• Beta blockers
• ACE inhibitors
• ARBs
• Aldosterone blockers
• Insulin
• Statins

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ACEIs, ARBs, CCBs, Statins, aldosterone
antagonists

• Reverse stiffening of aorta.
• Reverse or arrest aortic pressure augmentation.
• Reverse or arrest cardiac and renal damage.

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Hormones

• Do they work on the outside of the cell membrane
  by activating signal transduction pathways (such
  as insulin or epinephrine), or
• Do they cross cell membranes and modulate
  transcription of DNA in the nucleus (like thyroid
  and sex hormones).

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Cell does some thing fast with existing machinery
Epinephrine
Two Signal Transduction Pathways
Transcription factor
Protein
mRNA
Cell makes new machinery
Thyroid hormone
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Hormones

• Do they affect apoptosis (normal organ formation
  and maintenance) like glucose?
• Do they affect organ maturation (lung, brain
  blood vessels, GI tract) like glucose?

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Non-pregnant vs late pregnant mouse hearts. Note
hypertrophy and conduction disturbance (QRS
prolongation) in LP mouse heart.
Eghbali M (Trends Cardiovasc Med 200616285291)
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Cardiac hypertrophy requires activation of signal
transduction pathways for transcription and
translation. Different pathways are activated in
different types of hypertrophy. This is
demonstrated by production of different mRNA
profiles (gene fingerprinting).
Eghbali M (Trends Cardiovasc Med 200616285291)
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Pressure overload eg AS
Volume overload eg pregnancy or athletics
www.pitt.edu/super1/lecture/lec9691/018.htm
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Obesity
Two vicious cycles of type II DM
Inflammation
Glucotoxicity
Genetic predisposition
Insulin resistance
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Hyperglycemia
Atherosclerosis Nephropathy Retinopathy Neuropathy
Immune dysfunction Poor wound healing
Decreased insulin output
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Pancreatic beta cell damage
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Insulin can affect three different steps of
muscle glucose uptake
Wasserman DH Clin and Exp Pharm Phys 2005
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Insulin enables three distinct stages of glucose
utilization
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G
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Mitochondrion
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Hexokinase
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G6P
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arteriole
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Muscle cell
G
G
GLUT 4 transport protein
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G
Auto- regulation of microcirculation
G
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capillary
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Pre-capillary sphincter
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G glucose
Insulin mediated process
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Hyperglycemia cries wolf to the innate immune
system activating it when it is not needed and
weakening its capacity to respond to a real
infection.
portland.indymedia.org accessed on Google images
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Hyperglycemia damages (activates) the
endothelium.

• Hyperglycemia causes inflammation.

Reinhart K 2002, Dandona P 2005 J Clin Invest,
Dandona P 2003 Curr Drug Targets
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Hyperglycemia, sepsis and pre-eclampsia all
activate (damage) endothelium, white cells and
platelets, leading to white cell adhesion and
infiltration, thrombosis and edema (inflammation).
WBC
WBC
Hyperglycemia, sepsis or pre-eclampsia
Platelet
Platelets
Protein (edema)
Archer TL 2006 unpublished
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Endothelial cells send molecular signals to
surrounding smooth muscle
Insulin makes endothelium produce
Glucose makes endothelium produce
vasodilatory signals (NO, prostacyclin)
Vessel lumen
vasoconstrictive signals (thromboxane, endothelin)
Archer TL 2006 unpublished, Idea from Dandona P
2004
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Hyperglycemia damages mitochondria
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Chemo-osmosis in inner mitochondrial membrane
produces ATP
H gradient flowing through ATP synthase converts
ADP to ATP.
Electron transport chain creates H gradient
H
Outer mitochondrial membrane
H
H
ATP
Inner mitochondrial membrane
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Leakage of excess electrons to form ROS.
O2- superoxide
E-
Glucose
O2
E-
NADH and NADPH (electrons)
E-
Superoxides damage mitochondria.
Cytochromes of electron transport chain
Appropriate ATP generation
E-
½ O2
2H and 2e-
Hyperglycemia increases flow of electrons through
mitochondrial electron transport chain, with
increased leakage to form ROS, which damage
mitochondria.
H2O
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Hyperglycemia makes mitochondria peel out too
much energy produces destructive debris
Mitochondria exposed to too much NADPH (electron
energy).
Reactive oxygen species (ROS)
Google images
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Hormonal Yin and Yang

• Normal glucose metabolism is a balance between
• the anabolic effects of insulin and
• the catabolic effects of epinephrine, cortisol,
  glucagon and growth hormone.

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Absence / deficiency of insulin

• glucose does not enter muscle and liver cells and
  accumulates in the blood-?
• hyperglycemia and dehydration due to osmotic
  diuresis once renal threshold for glucose
  reabsorption is surpassed.

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Acute complications of insulin deficiency (and
Rx)

• DKA (associated with DM type 1).
• Hyperosmolar hyperglycemic nonketotic coma
  (associated with DM type 2).
• Hypoglycemia from excessive insulin Rx.

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Enormous dangers of hyperglycemia in pregnant
patients!

• HG alters DNA transcription, causing
• Diabetic embryopathy-- birth defects.
• Diabetic fetopathy macrosomia and organ
  immaturity for gestational age (e.g. lung).
• Placental vascular disease (IUGR, chronic
  malnutrition / hypoxia)
• Non-specific inflammation, vasoconstriction,
  coagulation and fibrosis.
• Decreased neutrophil / monocyte function.
• Neonatal hypoglycemia

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DKA in pregnancy (8 of diabetic pregnancies)

• Occurs in Type 1 DM.
• 30-70 chance of fetal death with DKA.
• Maternal acidosis appears to decrease uterine
  artery blood flow.

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Causes of DKA in pregnancy

• Patient noncompliance with insulin Rx.
• Infection.
• Steroid therapy for lung maturation in premies.
• Beta agonist tocolysis therapy stimulates
  glucagon release.

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Questions about DKA

• Why does a high glucose cause a low Na?
• Why do we give NS and not LR?
• Why can cerebral edema develop with rapid
  reduction of blood sugar, especially in kids?

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Hypoglycemia

• Always a danger, particularly with the tight
  glycemic control that is recommended nowadays
  before and during pregnancy.

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Chronic complications of hyperglycemia

• Microvascular complications (retinopathy,
  nephropathy and neuropathy).
• Macrovascular (MI, CVA, and PVD)
• Perioperative complications (of hyperglycemia)
• Poor wound healing.
• Increased infections.
• Increased neurological damage with brain trauma
  and CPB.
• Increased mortality in ICU patients.
• Worse results in acute MI patients, short and
  long term.

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Types of DM

• Type 1 genetic and autoimmune etiologies (often
  in the young). ABSENCE OF INSULIN.
• Type 2 obesity and genetic predisposition.
  RESISTANCE TO INSULIN.

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Gestational DM

• Appears in 4 of pregnancies. Possibly due to
  inability to make enough insulin to counteract
  the counteregulatory hormones which increase in
  pregnancyplacental lactogen, progesterone,
  placental GH and cortisol.
• Gestational DM tends to recur in subsequent
  pregnancies. Gestational DM increases risk for
  type 2 DM later in life.

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Pregestational DM

• Insulin requirements increase rapidly after the
  26th week of gestation. Insulin requirement at
  term is about 50 more than pre-pregnant
  requirements.
• Insulin requirements fall during first stage of
  labor, but rise during second stage of labor.
• Insulin requirement falls up to 40 the day
  after delivery. Placental hormones are
  diabetogenic.

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White classification

• Developed by Dr. Priscilla White in 1949shows
  positive correlation between duration of DM,
  severity of vascular complications and morbidity
  and mortality for the fetus.

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Hyperglycemia in pregnancy

• Women need to get in tight glycemic control
  BEFORE they get pregnant to minimize chance of
  fetal anomalies!
• Chestnuts textbook states that, only 36 of
  women with known pregestational DM receive
  appropriate medical care before conception.

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Hyperglycemia in pregnancy

• Hyperglycemia causes placental vascular
  degeneration an accelerated version of what
  happens (ASCVD) over the lifetime of a
  hyperglycemic individual.
• Leads to chronic placental insufficiency, IUGR
  and fetal distress with labor.
• Can cause IUFD.

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Hyperglycemia in pregnancy

• Organs do not mature properly due to effects on
  transcription, translation.
• Hyperglycemia causes premature birth, respiratory
  distress syndrome, intraventricular hemorrhage
  and hyperbilirubinemia.

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Hyperglycemia in pregnancy

• Causes macrosomia (big baby with risk of CPD or
  shoulder dystocia).

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Glycemic control during labor

• Prevents hyperinsulinemia in the fetus and
  rebound hypoglycemia in the fetus after delivery.
  
• Pediatrician may need to feed with D5W or start
  IV for glucose Rx in hypoglycemic neonate.

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Obstetric management

• A balancing act which tries to avoid BOTH
• Premature baby with immature organs (RDS or
  brain hemorrhage), and
• IUFD due to placental insufficiency late in
  gestation.

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Obstetric management

• Prevention of problems screening and glycemic
  control before conception.
• Universal screening for DM at 24-28 weeks.
• Skilled ultrasound at 24 weeks can pick up major
  malformations.
• Oral hypoglycemic agents were NOT used in
  pregnancy (this appears to be changing Xenakis
  research)

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Obstetric management

• Non-stress tests and other types of biophysical
  profiles are used to watch activity of fetus as
  term approaches.
• Amniotic fluid analysis for L/S ratio and PG can
  help determine surfactant levels (lung maturity).
• If lungs are mature, baby is delivered. If not,
  obstetrician can give betamethasone to assist
  lung maturation.
• Macrosomia would be a factor in favor of C/S.

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Anesthetic management

• Remember autonomic and somatic neuropathy
  (gastroparesis, orthostatic hypotension,
  positioning-related neuropathy, or attribution of
  DM neuropathy to regional anesthesia).
• Stiff joint syndromedifficult intubation due to
  stiff atlanto-occipital joint.
• High index of suspicion for problems with DM
  mothers.

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Thyroid disease in pregnancy

• Even mild maternal thyroid hormone deficiency may
  lead to neurodevelopment complications in the
  fetus.
• Universal screening? Not yet.

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Thyroid disease in pregnancy

• Think about it!
• Second most common endocrine problem area in
  pregnancy (after DM).

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Two syndromes in pregnancy

• Post-partum thyroiditis
• Gestational transient thyrotoxicosis

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Thyroid tests made simple

• Measure free T4 and TSH. Period.
• Someone who looks hyperthyroid should have a high
  free T4 and a non-measurable TSH.
• Someone who looks hypothyroid should have a low
  free T4 and a high TSH.

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Etiologies of hyperthyroidism (1 prevalence)

• Graves Disease in 70-90 of the cases.
• Autoimmune disease, with antibodies to TSH
  receptors, which turn them on.
• Thyroiditis5
• Toxic adenoma 5
• Toxic multinodular goiter5
• Rare causes TSH secreting tumor, thyroid
  ingestion, gestational trophoblastic tissue
  (hyperemesis gravidarum and hyperthyroidism can
  coexist), ectopic thyroid tissue.

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Medical and Surgical Therapy (non-pregnant
patients)

• RAI.
• Propylthiouracil or methimazole (block
  organification of iodine).
• Surgery (subtotal thyroidectomy).

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Thyroid storm (pregnant patient or not)

• Precipitated by infection, stress, surgery,
  childbirth, other acute disease.
• Rx with
• General support fluids, vitamins, cooling, O2,
  etc.
• Steroids (general support, blocks TSH release
  from pituitary and peripheral conversion of
  T3?T4).
• PTU (blocks organification of iodine).
• Na iodide (blocks release of T3 and T4 from
  thyroid gland). Give NaI one hour after starting
  PTU.
• Beta blockers.

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Hyperthyroidism in pregnancy

• No RAIwould enter fetus!
• PTU at low dose to minimize fetal thyroid
  suppression.
• Surgery reserved for when PTU fails.
• Preparation for surgery with agents above as
  for storm.
• Woman who has had thyroidectomy because of
  Graves disease can still have anti-thyroid
  antibodies (which act like TSH) and which cross
  the placenta and stimulate the fetal thyroid,
  causing fetal hyperthyroidism.

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Obstetric management of hyperthyroidism

• Beta blockers could precipitate labor.
• Fetal goiter could cause difficulty with birth
  and airway problems.

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Hypothyroidism in pregnancy

• Hx neck radiation or RAI Rx.
• Rx with lithium, iodine, amiodarone or
  antithyroid meds.
• Hx of thyroid surgery.

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Hypothyroidism in pregnancy

• TSH is best screening test for hypothyroidism.
• Rx is thyroid replacement.

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The End