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. The Beginning Oogenesis in Fetal Development

4. Meiosis in Oocytes 2N to 1N

5. Menstrual Cycle

6. ovulation

7. 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

8. 2 key cell types in the ovary: Theca cellsproduce androgens Granulosa cellsproduce estradiol + aromatase

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

10. Estrogen Lifecycle differences Reproductive years Estradiol (E2) Menopause Estrone (E1) Pregnancy Estriol (E3) Estradiol 10x as potent as estrone and 80 times as potent as estriol in estrogenic effect.

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

12. If fertilization occurs… Corpus Luteum makes HCG

13. 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.

15. 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

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

17. 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.

18. 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.

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

20. Conception & Implantation

21. Travel to uterus 3 days

22. Blastocyst

23. 3 Days to Implant

24. Major Pregnancy Hormones Estradiol HCG Insulin HPL Progesterone

25. 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

26. Insulin

27. 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

28. HPL increases as pregnancy progresses

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

30. Summary of pregnancy hormones

31. Clinical Correlation Ann is now 26 weeks pregnant and comes in for a check-up. She feels light- headed and dizzy from time to time, and she has some swelling in her ankles and feet. Her obstetrician performs the standard glucose tolerance test given to pregnant women between 24 and 28 weeks of pregnancy to screen for gestational diabetes:

32. 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

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

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

35. 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.

36. 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.

37. 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

38. Maternal Physiology

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

40. 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

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

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

43. 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

44. 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

45. Cardiac Output in Pregnancy

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

47. 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)

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

49. 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%

50. White Blood Cell Changes White blood cell count rises during pregnancy Differential is normal May be cortisol effect Immune system altered but not immunodeficient

51. Platelets Diluted in pregnancy Should still be within normal range Low platelets can represent a pathogenic state

52. Clinical Correlation Ann is now 26 weeks pregnant and comes in for a check-up. She feels light- headed and dizzy from time to time, and she has some swelling in her ankles and feet. Her obstetrician performs the standard glucose tolerance test given to pregnant women between 24 and 28 weeks of pregnancy to screen for gestational diabetes:

53. Laboratory Results Hematocrit 33%*36 - 48 % Platelets155,000150-440,000 White blood cells12,000* 4 -11,000

54. 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

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

62. Respiratory Changes Clinical Application 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

63. Arterial Blood Gas Non pregnant normal pHPAO 2 PACO 2 HCO 3 7.40 93-10035-40 23mEq/L Yours: pHPAO 2 PACO 2 HCO 3 7.421023218mEq/L

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

65. 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

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

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

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

69. 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

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

71. Renal Physiology

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

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

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

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

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

77. 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

78. 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

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

80. Sodium Balance Pregnancy

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

82. You note that you have developed cankles!

83. 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

84. Female Reproductive Physiology