Endocrine and obstetrics

1. Endocrine and obstetrics Tom Archer, MD, MBA UCSD Anesthesia

2. “Hormone” • From the Greek– “to stimulate or excite” • My version of the theme is “SIGNALING.”

5. Short term effect of glucose uptake into muscle Long term anabolic effects http://casestudies.med.utah.edu/med1/diabetes2/images/web/Insulin_signalling_pathways.jpg

6. Insulin is an ANABOLIC hormone • Insulin affects gene transcription, promoting tissue growth and health. • Insulin is NOT just about blood glucose control! Google images

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

8. Are hormones building new machinery (e.g. tissue growth)? (Slow) http://www.eng.vt.edu/warelab/images/Klages%20Machine%20Shop.jpg

9. Or are hormones turning on pre-existing machinery (e.g. glucose uptake into muscle)? (Fast)

10. 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)?

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

12. 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).

13. The sophisticated physician… • Will appreciate the multiple actions of hormones– many that are still unknown!

14. 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).

15. 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

16. ACEIs, ARBs, CCBs, Statins, aldosterone antagonists… • Reverse stiffening of aorta. • Reverse or arrest aortic pressure augmentation. • Reverse or arrest cardiac and renal damage.

17. 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).

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

19. 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?

20. Non-pregnant vs late pregnant mouse hearts. Note hypertrophy and conduction disturbance (QRS prolongation) in LP mouse heart. Eghbali M (Trends Cardiovasc Med 2006;16:285–291)

21. 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 2006;16:285–291)

22. Pressure overload eg AS Volume overload eg pregnancy or athletics www.pitt.edu/~super1/lecture/lec9691/018.htm

23. Obesity 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

24. Insulin can affect three different steps of muscle glucose uptake Wasserman DH Clin and Exp Pharm Phys 2005

25. Insulin enables three distinct stages of glucose utilization: G G G Mitochondrion G G Hexokinase G G6P G G arteriole G Muscle cell G G GLUT 4 transport protein G G Auto- regulation of microcirculation G G G G capillary G G G G G G G G G G G G Pre-capillary sphincter G G = glucose Insulin mediated process

26. 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

27. Hyperglycemia damages (“activates”) the endothelium. Hyperglycemia causes inflammation. Reinhart K 2002, Dandona P 2005 J Clin Invest, Dandona P 2003 Curr Drug Targets

29. 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

30. 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

31. Hyperglycemia damages mitochondria

32. 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

33. 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

34. 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

35. 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.

36. 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.

37. 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.

38. 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

39. 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.

40. 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.

41. 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?

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

43. 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.

44. 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.

45. Gestational DM: Appears in 4% of pregnancies. Possibly due to inability to make enough insulin to counteract the “counteregulatory hormones” which increase in pregnancy—placental 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.

46. 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”.

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

48. Hyperglycemia in pregnancy Women need to get in tight glycemic control BEFORE they get pregnant to minimize chance of fetal anomalies! Chestnut’s textbook states that, “…only 36% of women with known pregestational DM receive appropriate medical care before conception.”

49. 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.

50. 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.