1. Female Reproductive Physiology Hope A. Ricciotti, M.D. Associate Professor of Obstetrics, Gynecology and Reproductive Biology Beth Israel Deaconess Medical Center Harvard Medical School

2. At the end of this session you should be able to... Describe hormonal changes of the menstrual cycle. List steps from conception to early pregnancy. Describe major physiologic changes in systems (cardiovascular, renal, hematologic, pulmonary, GI, and breast) during pregnancy. Provide physiologic rationalizations for these changes.

3. Menstrual Cycle

4. ovulation

5. Menstrual Cycle Median duration is 28 days 21-35 days considered normal Luteal phase is constant at 14 days Variability in length of follicular phase

6. 2 key cell types in the ovary: Theca cellsproduce androgens Granulosa cellsproduce estradiol + aromatase

7. Estrogen Production Theca cells produce androgens Granulosa cells produce estradiol + aromatase

8. Fecundity Rate by Age Fecundity Rates by Age 35-39 years30% 27-34 years40% 19-26 years50%

9. If fertilization occurs… Corpus Luteum makes HCG

10. HCG Hormone Composed of 2 subunits – alpha and beta. The alpha subunit is identical to other pituitary hormones – TSH and LH. The beta subunit is more specific.

12. HCG -Pregnancy Testing Produced by the trophoblastic layer shortly after fertilization occurs. Detectable in bloodstream 8 days after conception Detectable in urine 10 days after conception

13. Antibody to HCG plus Color Change Antibody Monoclonal mouse anti-hcg enzyme conjugate Polyclonal anti-hcg antibodies Antimouse antibodies

14. Clinical Correlation Your patient, Ann, is trying to get pregnant. On the day that she ovulates, day 14 of her menstrual cycle, she and her partner have intercourse. She purchases a pregnancy test from the drugstore the next day. The test is negative. She checks again a week later -- still negative.

15. She checks again two weeks later, on the day she should be due for her period, and sees a faint positive line. She checks again a few days – just to be sure - and the line is now strongly positive.

16. Thought question Why is the pregnancy test initially negative, then faintly positive, then strongly positive? What is a physiologic explanation for these findings?

17. Conception & Implantation

18. Travel to uterus 3 days

19. Blastocyst

20. 3 Days to Implant

21. Major Pregnancy Hormones Estradiol HCG Insulin HPL Progesterone

22. Insulin Anabolic hormone Promotes uptake of glucose by cells A large molecule that does not pass the placenta Pregnancy is a state of relative insulin resistance

23. HPL - Anti-insulin Human placental lactogen Produced by placenta Structure and function similar to growth hormone Modifies metabolic state of pregnancy –creates insulin resistance –results in lypolysis –facilitates glucose transfer to fetus –Glucose passes placenta by diffusion

24. HPL increases as pregnancy progresses

25. Progesterone A smooth muscle relaxant Keeps uterus quiescent until term Has ‘side effects’ all over the body

26. Summary of pregnancy hormones

27. Clinical Correlation Ann is now 26 weeks pregnant and comes in for a check-up. She feels well. Her obstetrician performs a (routine) glucose tolerance test at 24 weeks of pregnancy to screen for gestational diabetes:

28. Laboratory results Three hour glucose tolerance test (mg/dl) fasting 110* (105) 1 hr170 (190) 2 hr200* (165) 3 hr130(145) 2/4 abnormal values gives diagnosis of gestational diabetes

29. Treatment Gestational Diabetes Exercise Medical Therapy –Insulin –Oral Agents Peripartum Management –Goal 70-90 mg/dl –Avoid maternal hyperglycemia –Insulin if required

30. Thought question Why did her obstetrician wait until the second trimester to do a glucose tolerance test for gestational diabetes?

31. Gestational Diabetes Why wait to screen? HPL promotes insulin resistance and lypolysis Favors placental transfer of glucose to fetus by reducing maternal use Human Placental Lactogen increases as pregnancy progresses If you screen too early in pregnancy you will miss the diagnosis

32. HPL Increases as pregnancy progresses

33. Diabetes and Pregnancy If you test positive for diabetes in the first trimester that is actually Type II diabetes 50% of women who have gestational diabetes go on to develop type II diabetes later in life Gestational diabetes is a warning signal that you are at risk and can motivate women to make lifestyle changes

34. Clinical Correlation A pregnant woman with insulin dependent gestational diabetes presents near her due date (39 weeks) in active labor. She has not been regularly taking her insulin because her copays for syringes, test strips and medication are too high for her to afford. She reports that her glucose levels have been consistently high without her insulin.

35. This is her third baby and labor progresses quickly. Before you’ve had a chance to test her glucose or start insulin, she has a normal vaginal delivery without complication. Her baby weighs 9 pounds.

36. At 30 minutes of life, the baby has a seizure. The pediatrician is called and finds the baby hypoglycemic, which is likely the cause of the seizure. She treats the baby with intravenous glucose. What could be a physiologic explanation for the hypoglycemia? Thought question

37. Physiologic Explanation Mother’s diabetes not well controlled, resulting in high maternal glucose levels Fetus exposed to high levels of glucose in utero because glucoses passes freely via placenta by diffusion to fetus Insulin is large molecule that does not pass placenta Fetus makes large amounts of insulin to regulate its own glucose levels

38. At birth, maternal glucose supply abruptly cut off when umbilical cord cut Baby still had large amounts of insulin in its circulation After 30 minutes, high insulin results in a very low glucose level in baby since supply of glucose from mother had been severed

39. Maternal Physiology

40. Cardiovascular Changes in Pregnancy Maternal total body water 6-8 liters Fetus, placenta, amniotic fluid 3.5 liters Total blood volume50% Red cell mass35%

41. Mechanism of Sodium and Water Retention Concentrations of renin and angiotensin are increased in response to vasorelaxation (progesterone effect) Serum level sodium decreases during a normal pregnancy Resetting of the osmotic thresholds for both thirst and antidiuretic hormone release

42. Pregnant women are thirsty Stimulates water intake and dilution of body fluids. Maternal interstitial volume shows its greatest increase in the last trimester.

43. Maternal Blood Volume Plasma volume increases 50% Red cell mass increases 30%-40% Creates a dilutional anemia

44. Increased Heart Rate in Pregnancy Exact mechanism unknown Thought to be a direct effect of hormones on pacemaker in heart Increased 15-20 beats per minute

45. Frank Starling Law and Pregnancy The greater the end diastolic volume, the greater the stroke volume Cardiac Output = SV x HR Cardiac Output increases significantly in pregnancy, reaching a peak at 24 weeks

46. Cardiac Output in Pregnancy

47. What causes in the increase in cardiac output in pregnancy? 1.Increased SV 2.Increased HR 3.Both SV and HR increase

48. Increased Maternal Blood Volume Serves metabolic needs of fetus Increased perfusion of others organs, especially kidneys Compensates for maternal blood loss delivery (vaginal delivery is 500 ml, cesarean delivery about 1000ml)

49. Decreased Peripheral Resistance Progesterone is smooth muscle relaxant Vasorelaxant Results in decreased peripheral resistance/lower blood pressure in pregnancy

50. Summary Cardiovascular Changes in Pregnancy Blood pressure  6-10 mm Hg Heart Rate  12-18 beats/min Stroke volume  10-30% Cardiac Output  33-45%

51. Clinical Correlation Ann is now 32 weeks pregnant and comes in for a check-up. She feels light- headed and dizzy when she goes from sitting to standing, and she has some swelling in her ankles and feet. You decide to check for anemia.

52. Laboratory Results Hematocrit 33%*36 - 48 %

53. What are potential physiologic explanations for her dizziness and light- headedness? Might her anemia (hematocrit of 33%) be related to these symptoms? How? Thought Questions

54. Why dizzy/light headed? Physiologic anemia (plasma volume expansion) – probably not related Blood pressure lower - vasorelaxation (progesterone effect) more likely explanation

55. Respiratory Changes in Pregnancy Progesterone levels drive hyperventilation Subjective sense of dyspnea is common Respiratory rate is unchanged Chest wall mechanics are changed

56. Chest Wall Changes Intercostal angle increases from 70 to 100° Transverse diameter of chest increases 2 cm Chest circumference increases by 5-7 cm Lung compliance does not change

57. Respiratory Changes in Pregnancy

58. Pulmonary Function Summary Tidal volume  40% Minute ventilation  40% Respiratory rateunchanged

59. Clinical Correlation Ann notes that she gets quickly winded, even while walking up a few stairs. You measure her respiratory rate and it is normal.

60. Thought Questions: What is the most likely reason for her shortness of breath? 1.Anemia 2.Pulmonary Embolism 3.Central effect

61. Respiratory System Dyspnea is common even in early pregnancy, before the mechanical effects of an enlarging uterus become significant. Dyspnea during early pregnancy is thought to be a central (“controller”) effect caused by progesterone (which is a respiratory stimulant).

62. Thought Question: Is minute ventilation increased or decreased in pregnancy? 1.Increased 2.Decreased

63. Minute Ventilation Formula Volume of air that can be inhaled or exhaled in one minute Tidal Volume x Respiratory Rate (increased)(unchanged) Increased in pregnancy due to TV

64. Respiratory Changes Clinical Correlation Ann feels short of breath, even while walking up a few stairs. Her respiratory rate is normal. An arterial blood gas is done to evaluate this.

65. Arterial Blood Gas Non pregnant normal pHPAO 2 PACO 2 HCO 3 7.40 93-10035-40 23mEq/L Ann’s: pHPAO 2 PACO 2 HCO 3 7.421023218mEq/L

66. Choose correct acid base status 1.Metabolic Alkalosis 2.Respiratory alkalosis

67. This is a respiratory alkalosis from hyperventilation with renal compensation pHPaO 2 PaCO 2 HCO 3 7.42100-10532 18mEq/L

68. A Well Designed System Total oxygen consumption is increased Hyperventilation and respiratory alkalosis Cardiorespiratory responses are so efficient that: –Arteriovenous difference actually DECREASES

69. A-aO2 difference The difference in partial pressure of oxygen between the alveolus and the arterial blood. An abnormally large difference is characteristic of problems with the gas exchanger. In pregnancy, we have the opposite

70. Gastrointestinal Changes Progesterone is a smooth muscle relaxant Decreased GI motility Longer GI transit time Relaxation of the lower esophageal sphincter

71. GI Changes in Pregnancy Constipation Reflux Longer time for gastric emptying

72. Gastrointestinal Changes Clinical Correlation At 28 weeks, Ann notes worsening constipation, and some burning in her chest in bed at night.

73. Constipation Reduced GI motility due to progesterone Mechanical effect of enlarging uterus on GI motility Prolonged GI transit time, more water absorbed, stool harder Iron supplements compounds issues Most pregnant women are constipated

74. Reflux Relaxation of lower esophageal sphincter Slower stomach emptying time Elevation of stomach by enlarged uterus

75. Renal Physiology

76. Renal Changes in Pregnancy Renal blood flow increases 25%-50% –Increased CO –Decreased vascular resistance Glomerular Filtration Rate increases 50%

77. Pregnancy Changes in Kidney Kidney Size increases Urinary stasis - progesterone Increased susceptibility to infection from stasis

78. Is filtration fraction increased or decreased in pregnancy? 1.Increased 2.Decreased

79. Filtration Fraction in Pregnancy Filtration Fraction = GFR/RPF Increased filtration fraction –Increase in GFR > Renal blood flow

80. Substance Excreted in Urine Determined by the equation: (filtered) – (reabsorbed) + (secreted)

81. Pregnant Urinalysis Glycosuria may not be abnormal Trace proteinuria may not be abnormal Explained by increased GFR with overwhelming of tubular reabsorption capacity

82. Clinical Correlation Ann finds herself urinating frequently. When she does go, though, she notices that she urinates only small amounts. You check a urinalysis, culture, and BUN/creatinine, and electrolytes

83. Results BLOODnormal range BUN5 mg/dL 6 - 20 CR 0.3 mg/dL 0.4 - 1.1 Na132 meq/l133-145 URINE Blood neg Nitrite neg Protein trace mg/dL Glucose trace mg/dL Ketone 15 mg/dL Leukocytes neg

84. Why is BUN and CR lower in pregnancy? 1.Increased GFR 2.Increased Renal plasma flow 3.Both 1 and 2

85. Sodium Balance Pregnancy

86. Renin-Angiotensin-Aldosterone Pregnancy Decreased resistance/BP in pregnancy stimulate this system Net retention of sodium and water in pregnancy

87. You note that you have developed cankles!

88. Why do you have cankles? 1.Obstructed venous return 2.Decreased oncotic pressure 3.Retention of Sodium and Water 4.All of the above 5.None of the above

89. Female Reproductive Physiology