Title: Endocrine and obstetrics
1Endocrine and obstetrics
- Tom Archer, MD, MBA
- UCSD Anesthesia
2Hormone
- From the Greek to stimulate or excite
- My version of the theme is SIGNALING.
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5Short 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
6Insulin is an ANABOLIC hormone
- Insulin affects gene transcription, promoting
tissue growth and health.
Insulin is NOT just about blood glucose control!
Google images
7Insulin
- Anticoagulant
- Vasodilatory
- Anti-inflammatory
- Anabolic
- Insulin even reduces augmentation index!
8Are hormones building new machinery (e.g. tissue
growth)? (Slow)
http//www.eng.vt.edu/warelab/images/Klages20Mach
ine20Shop.jpg
9Or are hormones turning on pre-existing
machinery (e.g. glucose uptake into
muscle)? (Fast)
10Hormones
- 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)?
11Hormones
- Can have multiple sites of action and
- Multiple time courses and mechanisms of action.
12Examples 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).
13The sophisticated physician
- Will appreciate the multiple actions of hormones
many that are still unknown!
14Complex 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).
15Many 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
16ACEIs, ARBs, CCBs, Statins, aldosterone
antagonists
- Reverse stiffening of aorta.
- Reverse or arrest aortic pressure augmentation.
- Reverse or arrest cardiac and renal damage.
17Hormones
- 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).
18Cell does some thing fast with existing machinery
Epinephrine
Two Signal Transduction Pathways
Transcription factor
Protein
mRNA
Cell makes new machinery
Thyroid hormone
19Hormones
- Do they affect apoptosis (normal organ formation
and maintenance) like glucose? - Do they affect organ maturation (lung, brain
blood vessels, GI tract) like glucose?
20Non-pregnant vs late pregnant mouse hearts. Note
hypertrophy and conduction disturbance (QRS
prolongation) in LP mouse heart.
Eghbali M (Trends Cardiovasc Med 200616285291)
21Cardiac 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)
22Pressure overload eg AS
Volume overload eg pregnancy or athletics
www.pitt.edu/super1/lecture/lec9691/018.htm
23Obesity
Two vicious cycles of type II DM
Inflammation
Glucotoxicity
Genetic predisposition
Insulin resistance
1
Hyperglycemia
Atherosclerosis Nephropathy Retinopathy Neuropathy
Immune dysfunction Poor wound healing
Decreased insulin output
2
Pancreatic beta cell damage
24Insulin can affect three different steps of
muscle glucose uptake
Wasserman DH Clin and Exp Pharm Phys 2005
25Insulin enables three distinct stages of glucose
utilization
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Mitochondrion
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Hexokinase
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G6P
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arteriole
G
Muscle cell
G
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GLUT 4 transport protein
G
G
Auto- regulation of microcirculation
G
G
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capillary
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Pre-capillary sphincter
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G glucose
Insulin mediated process
26Hyperglycemia 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
27Hyperglycemia 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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29Hyperglycemia, 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
30Endothelial 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
31Hyperglycemia damages mitochondria
32Chemo-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
33Leakage 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
34Hyperglycemia makes mitochondria peel out too
much energy produces destructive debris
Mitochondria exposed to too much NADPH (electron
energy).
Reactive oxygen species (ROS)
Google images
35Hormonal 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.
36Absence / 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.
37Acute 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.
38Enormous 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
39DKA 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.
40Causes of DKA in pregnancy
- Patient noncompliance with insulin Rx.
- Infection.
- Steroid therapy for lung maturation in premies.
- Beta agonist tocolysis therapy stimulates
glucagon release.
41Questions 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?
42Hypoglycemia
- Always a danger, particularly with the tight
glycemic control that is recommended nowadays
before and during pregnancy.
43Chronic 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.
44Types of DM
- Type 1 genetic and autoimmune etiologies (often
in the young). ABSENCE OF INSULIN. - Type 2 obesity and genetic predisposition.
RESISTANCE TO INSULIN.
45Gestational 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.
46Pregestational 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.
47White 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.
48Hyperglycemia 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.
49Hyperglycemia 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.
50Hyperglycemia in pregnancy
- Organs do not mature properly due to effects on
transcription, translation. - Hyperglycemia causes premature birth, respiratory
distress syndrome, intraventricular hemorrhage
and hyperbilirubinemia.
51Hyperglycemia in pregnancy
- Causes macrosomia (big baby with risk of CPD or
shoulder dystocia).
52Glycemic 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.
53Obstetric 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.
54Obstetric 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)
55Obstetric 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.
56Anesthetic 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.
57Thyroid disease in pregnancy
- Even mild maternal thyroid hormone deficiency may
lead to neurodevelopment complications in the
fetus. - Universal screening? Not yet.
58Thyroid disease in pregnancy
- Think about it!
- Second most common endocrine problem area in
pregnancy (after DM).
59Two syndromes in pregnancy
- Post-partum thyroiditis
- Gestational transient thyrotoxicosis
60Thyroid 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.
61Etiologies 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.
62Medical and Surgical Therapy (non-pregnant
patients)
- RAI.
- Propylthiouracil or methimazole (block
organification of iodine). - Surgery (subtotal thyroidectomy).
63Thyroid 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.
64Hyperthyroidism 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.
65Obstetric management of hyperthyroidism
- Beta blockers could precipitate labor.
- Fetal goiter could cause difficulty with birth
and airway problems.
66Hypothyroidism in pregnancy
- Hx neck radiation or RAI Rx.
- Rx with lithium, iodine, amiodarone or
antithyroid meds. - Hx of thyroid surgery.
67Hypothyroidism in pregnancy
- TSH is best screening test for hypothyroidism.
-
- Rx is thyroid replacement.
68The End